Substituted aryl and heteroaryl compounds as E-type prostaglandin antagonists

ABSTRACT

Compounds of the formula I;  
                 
 
     useful for the treatment of pain wherein A, Z, B, R 1 , X and D are as defined in the specification, methods of making such compounds, methods of using such compounds and pharmaceutical compositions containing such compounds

[0001] This is a continuation of prior application Ser. No. 09/811,779,filed Mar. 19, 2001, pending which is a continuation of priorapplication Ser. No. 09/505,969, filed Feb. 17, 2000 abandoned, which isa division of application Ser. No. 09/183,578, filed Oct. 30, 1998, nowPat. No. 6,057,345, which is a division of application Ser. No.08/673,878, filed Jul. 2, 1996, now Pat. No. 5,834,468.

[0002] This invention relates to novel, aromatic compounds andpharmaceutically-acceptable salts thereof which possess usefulpharmacological properties. More particularly the compounds of theinvention are antagonists of the pain enhancing effects of E-typeprostaglandins. The invention also relates to processes for themanufacture of the aromatic compounds and pharmaceutically-acceptablesalts thereof; to novel pharmaceutical compositions containing them; andto use of the compounds in pain relief.

[0003] The compounds of the invention are useful in the treatment ofpain such as the pain associated with joint conditions (such asrheumatoid arthritis and osteoarthritis), postoperative pain,post-partum pain, the pain associated with dental conditions (such asdental caries and gingivitis), the pain associated with bums (includingsunburn), the treatment of bone disorders (such as osteoporosis,hypercalcaemia of malignancy and Paget's disease), the pain associatedwith sports injuries and sprains and all other painful conditions inwhich E-type prostaglandins wholly or in part play a pathophysiologicalrole.

[0004] Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates arethe main classes of drugs in pain relief. However both possessundesireable side effects. NSAIDS are known to cause gastrointestinalirritation and opiates are known to be addictive.

[0005] We have now found a class of compounds structurally different toNSAIDS and opiates, and useful in the relief of pain.

[0006] The compounds of the invention may also possessanti-inflammatory, anti-pyretic and anti-diarrhoeal properties and beeffective in other conditions in which prostaglandin E₂ (PGE₂) wholly orin part plays a pathophysiological role.

[0007] According to the invention there is provided a compound of theformula I;

[0008] wherein:

[0009] A is an optionally substituted:

[0010] phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl,thienyl, thiazolyl, oxazolyl, thiadiazolyl having at least two adjacentring carbon atoms or a bicyclic ring system of the formula:

[0011] wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphur oroxygen and H is nitrogen or CH;

[0012] provided that the —Z—B—R¹ and —X—D linking groups are positionedin a 1,2 relationship to one another on ring carbon atoms and the ringatom positioned ortho to the —X— linking group (and therefore in the3-position relative to the —Z— linking group) is not substituted;

[0013] B is an optionally substituted:

[0014] phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl,isoxazole, pyrazole, furyl, pyrrolyl, imidazolyl, pyrazinyl,pyridazinyl, pyrimidyl, pyridone, pyrimidone, pyrazinone orpyridazinone;

[0015] D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl or phenyl;

[0016] R¹ is positioned on ring B in a 1,3 or 1,4 relationship with the—Z— linking group in 6-membered rings and in a 1,3-relationship with the—Z— linking group in 5-membered rings and is carboxy, carboxyC₁₋₃ alkyl,tetrazolyl, tetrazolylC₁₋₃alkyl, tetronic acid, hydroxamic acid,sulphonic acid, or R¹ is of the formula —SO₂NHR^(e) wherein R^(e) ishydrogen or C₁₋₆alkyl; or R¹ is of the formula (IIA), (IIB) or (IIC):

[0017]  wherein X″ is CH or nitrogen, Y is oxygen or sulphur Y′ isoxygen or NH, and Z is CH₂, NH or oxygen provided that there is no morethan one ring oxygen and there are at least two ring heteroatoms; or R¹is of the formula —CONR^(a)R^(a1) or —C₁₋₃alkylCONR^(a)R^(a1) whereinR^(a) is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₅₋₇cycloalkenyl or C₅₋₇cycloalkenylC₁₋₃alkyl and R^(a1) is hydrogen,hydroxy or optionally substituted: C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₂₋₆alkenyl, C₃₋₇cycloalkylC₂₋₆alkynyl, C₅₋₇cycloalkenyl,C₃₋₇cycloalkenylC₁₋₆alkyl, C₅₋₇cycloalkenylC₂₋₆alkenyl,C₅₋₇cycloalkenylC₂₋₆alkynyl, 5- or 6-membered heteroaryl, 5- or6-membered heteroarylC₁₋₆alkyl, 5- or 6-membered saturated or partiallysaturated heterocyclyl or 5- or 6-membered saturated or partiallysaturated heterocyclylC₁₋₆alkyl; or wherein R^(a) and R^(a1) togetherwith the amide nitrogen to which they are attached (NR^(a)R^(a1)) forman amino acid residue or ester thereof; or R¹ is of the formula—CONHSO₂R^(b) or —C₁₋₃alkylCONHSO₂R^(b) wherein R^(b) is optionallysubstituted: C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₂₋₆alkenyl,C₃₋₇cycloalkylC₂₋₆alkynyl, C₅₋₇cycloalkenyl, C₃₋₇cycloalkenylC₁₋₆alkyl,C₅₋₇cycloalkenylC₂₋₆alkenyl, C₅₋₇cycloalkenylC₂₋₆alkynyl, 5- or6-membered heteroaryl, 5- or 6-membered heteroylarC₁₆alkyl, phenyl,phenylC₁₋₆alkyl, 5- or 6-membered saturated or partially saturatedheterocyclyl or 5- or 6-membered saturated or partially saturatedheterocyclylC₁₋₆alkyl or R¹ is of the formula —CONR^(a)N(R^(c))R^(d) or—C₁₋₃alkylCONR^(a)N(R^(c))R^(d) wherein R^(a) is as hereinabove defined,R^(c) is hydrogen or C₁₋₆alkyl and R^(d) is hydrogen, hydroxy oroptionally substituted: C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₂₋₆alkenyl,C₃₋₇cycloalkylC₂₋₆alkynyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₆alkyl,C₅₋₇cycloalkenylC₂₋₆alkenyl, C₅₋₇cycloalkenylC₂₋₆alkynyl, 5- or6-membered heteroaryl, 5- or 6-membered heteroarylC₁₋₆alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆alkyl, orR^(c) and R^(d), together with the nitrogen atom to which they areattached, form a 4 to 8-membered saturated or partially saturatedheterocyclic ring or form an amino acid residue or ester thereof;

[0018] X is —OCH₂—, —SCH₂—, —CH₂CH₂—, CH₂—, —O—, —S— or —NH(R⁴)CH₂wherein the left hand atom is attached to A and the right hand atom isattached to D;

[0019] Z is of the formula —CH(R³)CH(R³)N(R²)—, —N(R²)CH(R³)—,—CH(R³)P¹—, —(CH(R³))m— or —CH(R³)N(R²)—

[0020] wherein

[0021] R² is hydrogen, C₁₋₆alkyl (optionally substituted by hydroxy,cyano, nitro, amino, halo, C₁₋₄alkanoyl, C₁₋₁₄alkoxy or trifluoromethyl)C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl,C₃₋₆cycloalkylC₂₋₃alkenyl, C₅₋₆cycloalkenyl, C₅₋₆cycloalkenylC₁₋₃alkyl,C₅₋₆cycloalkenylC₂₋₃alkenyl, phenyl, phenylC₁₋₃alkyl or 5- or 6-memberedheteroarylC₁₋₃alkyl;

[0022] R³ is hydrogen or C₁₋₄alkyl;

[0023] P¹ is oxygen or sulphur, m is 2 or 3 and R⁴ is hydrogen orC₁₋₄alkyl and wherein the left hand atom is attached to A and the righthand atom is attached to B; provided that when Z is —CH(R³)N(R²)— or—(CH(R³))m—, X is not —OCH₂—; and N-oxides of —NR² where chemicallypossible;

[0024] and S-oxides of sulphur containing rings where chemicallypossible;

[0025] and pharmaceutically acceptable salts and in vivo hydrolysableesters and amides thereof, excluding4-[4-acetyl-2-benzyl-3-hydroxyphenoxymethyl]-3-methoxybenzoic acid.

[0026] A 5- or 6-membered heteroaryl ring system is a monocyclic arylring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms areselected from nitrogen, oxygen and sulphur.

[0027] A 5- or 6-membered saturated or partially saturated heterocyclic(heterocyclyl) ring is a ring system having 5 or 6 ring atoms wherein 1,2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulphur.

[0028] Particular 5- or 6-membered monocyclic heteroaryl rings includepyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl,furyl and oxazolyl.

[0029] Particular 5- or 6-membered saturated or partially saturatedheterocyclic ring ring systems include pyrrolidinyl, pyrrolinyl,imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

[0030] The linking group —CH(R³)N(R²)CH(R³)— includes —CH₂N(R²)CH(Me)—,—CH₂N(R²)CH_(2—)and —CH(Me)N(R²)CH₂—.

[0031] The linking group —CH(R³)CH(R³)N(R²)— includes —CH₂CH(Me)N(R²)—,—CH(Me)CH₂N(R²)— and —CH₂CH₂N(R²)—.

[0032] The linking group —(CH(R³))m— includes —(CH(Me))₂—, —CH₂CH(Me)—,—CH(Me)CH₂— and —(CH₂)₃—.

[0033] Particular substituents for ring carbon atoms in A and D includehalo, trifluoromethyl, nitro, hydroxy, amino, C₁₋₄alkylamino,diC₁₋₄alkylamino, cyano, C₁₋₆alkoxy, —S(O)_(p)C₁₋₆alkyl (p is 0, 1 or2), C₁₋₆alkyl (optionally substituted by hydroxy, amino, halo, nitro orcyano), —S(O)_(p)CF₃ (p=0, 1 or 2), carbamoyl, C₁₋₄alkylcarbamoyl,di(C₁₋₄alkyl)carbamoyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₂₋₄alkenylamino,N—C₂₋₄alkenyl-N—C₁₋₄alkylamino, di-C₂₋₄alkenylamino,S(O)_(p)C₂₋₆alkenyl, C₂₋₄alkenylcarbamoyl, N—C₂₋₄alkenyl-N-alkylamino,di-C₂₋₄alkenylcarbamoyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₅₋₇cycloalkenylC₂₋₃alkenyl, C₅₋₇cycloalkenylC₂₋₃alkynyl,C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoylamino,C₁₋₄alkanoyl(N—C₁₋₄alkyl)amino, C₁₋₄alkanesulphonamido,benzenesulphonamido, aminosulphonyl, C₁₋₄alkylaminosulphonyl,di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyloxy,C₁₋₆alkanoyl, formylC₁₋₄alkyl, trifluoroC₁₋₃alkylsulphonyl,hydroxyiminoC₁₋₆alkyl, C₁₋₄alkoxyiminoC₁₋₆alkyl C₁₋₆alkylcarbamoylamino,oxazolyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl and pyridazinyl.

[0034] Where a ring nitrogen atom in A can be substituted withoutbecoming quaternised, it is unsubstituted or substituted by C₁₋₄alkyl.

[0035] Particular substituents for ring carbon atoms in B include halo,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, trifluoromethyl, nitro,hydroxy, C₁₋₆alkoxy, C₁₋₆alkyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano, —S(O)_(p)C₁₋₆alkyl (p is 0, 1 or 2),carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

[0036] Where a ring nitrogen atom in B can be substituted withoutbecoming quaternised, it is unsubstituted or substituted by C₁₋₄alkyl.

[0037] Particular substituents for optionally substituted groups inR^(a1) R^(b) and R^(d) include those mentioned above for ring A.

[0038] Particular substituents for carbon atoms in optionallysubstituted groups in R^(a1) include halo, hydroxy, C₁₋₄alkyl, nitro,cyano, amino, carboxy, trifluoromethyl, C₁₋₄alkoxy, C₃₋₇cycloalkyl,C₅₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₃alkyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenylC₂₋₃alkenyl andC₁₋₄alkoxycarbonyl. Particular substituents for optionally substitutedgroups in R^(b) include halo, trifluoromethyl, nitro, C₁₋₄alkyl,hydroxy, amino, cyano, amino, C₁₋₆alkoxy, S(O)_(p)C₁₋₆alkyl (p is 0, 1or 2), carbamoyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄alkyl)carbamoyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₃alkyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenylC₂₋₃alkenyl,C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoylamino,C₁₋₄alkanoyl(N—C₁₋₄alkyl)amino, C₁₋₄alkanesulphonamido,benzenesulphonamido, aminosulphonyl, C₁₋₄alkylaminosulphonyl,di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyloxy,C₁₋₆alkanoyl, formylC₁₋₄alkyl, hydroxyiminoC₁₋₆alkyl,C₁₋₄alkoxyiminoC₁₋₆alkyl and C₁₋₆alkylcarbamoylamino.

[0039] The term alkyl when used herein includes straight chain andbranched chain substituents for example methyl, ethyl, n-propyl,isopropyl, n-butyl and isobutyl and functional groups on alkyl chainsmay be anywhere on the chain, for example hydroxyiminoC₁₋₆alkyl includes1-(hydroxyimino)propyl and 2-(hydroxyimino)propyl.

[0040] Examples of C₁₋₆alkoxycarbonyl are methoxycarbonyl,ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC₁₋₃alkyl arecarboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl;examples of C₁₋₆alkoxycarbonylC₁₋₃alkyl are methoxycarbonylmethyl,ethoxycarbonylmethyl and methoxycarbonylethyl; examples oftetrazolylC₁₋₃alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examplesof C₁₋₄alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples ofC₂₋₆alkenyl are vinyl and allyl; examples of C₂₋₆alkynyl are ethynyl andpropynyl; examples of C₁₋₄alkanoyl are formyl, acetyl, propionyl andbutyryl; examples of halo are fluoro, chloro, bromo and iodo; examplesof C₁₋₄alkylamino are methylamino, ethylamino, propylamino andisopropylamino; examples of di(C₁₋₄alkyl)amino are dimethylamino,diethylamino and ethylmethylamino; examples of —S(O)_(p)C₁₋₄alkyl aremethylthio, methylsulphinyl and methylsulphonyl; examples ofC₁₋₄alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples ofdi(C₁₋₁₄alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl andethylmethylcarbamoyl; examples of C₁₋₆alkyl are methyl, ethyl, propyland isopropyl; examples of C₃₋₇cycloalkyl are cyclopropyl, cyclobutyland cyclohexyl; examples of C₃₋₇cycloalkylC₁₋₃alkyl arecyclopropylmethyl and cyclohexylmethyl; examples ofC₃₋₇cycloalkylC₂₋₃alkenyl are cyclopropylethenyl andcyclopentylpropenyl; examples of C₃₋₇cycloalkylC₂₋₃alkynyl arecyclopropylethynyl and cyclopentylethynyl; examples of C₅₋₇alkenyl arecyclopentenyl and cyclohexenyl; examples of C₅₋₇cycloalkenylC₁₋₃alkylare cyclopentenylmethyl and cyclohexenylmethyl; examples ofC₅₋₇cycloalkenylC₂₋₃alkenyl are cyclohexenylethenyl andcycloheptenylethenyl; examples of C₅₋₇cycloalkenylC₂₋₃alkynyl arecyclopentenylethynyl and cyclohexenylethynyl; examples ofC₁₋₄alkoxycarbonylamino are methoxycarbonylamino andethoxycarbonylamino; examples of C₁₋₄alkanoylamino are acetamido andpropionamido; examples of C₁₋₄alkanoyl(N—C₁₋₄alkyl)amino areN-methylacetamido and N-methylpropionamido; examples ofC₁₋₄alkanesulphonamido are methanesulphonamido and ethanesulphonamido;examples of C₁₋₄alkylaminosulphonyl are methylaminosulphonyl andethylaminosulphonyl; examples of di(C₁₋₄alkyl)aminosulphonyl aredimethylaminosulphonyl, diethylaminosulphonyl andethylmethylaminosulphonyl; examples of C₁₋₄alkanoyloxy are acetyloxy andpropionyloxy; examples of formylC₁₋₄alkyl are formylmethyl and2-formylethyl; examples of hydroxyiminoC₁₋₆alkyl are hydroxyiminomethyland 2-(hydroxyimino)ethyl; and examples of C₁₋₄alkoxyiminoC₁₋₆alkyl aremethoxyiminomethyl, ethoxyiminomethyl and 2-(methoxyimino)ethyl.

[0041] Suitable ring systems of the formula (IIA), (IIB) or (IIC)include 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl,3-thioxo-2,3-dihydro-1,2,4-oxadiazol-5-yl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl,5-oxo-4,5-dihydro-1,2,4-triazol-3-yl, 3-oxo-2,3-dihydroisoxazol-5-yl,5-oxo-1,5-dihydroisoxazol-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.

[0042] Amino acid residues formed from R^(a) and R^(a1) together withthe amide nitrogen to which they are attached and esters thereof includefor example radicals of the formula —NH—CH(R^(c))—COOR^(d) wherein R^(c)is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl,phenylC₁₋₃alkyl, 5- or 6-membered heteroaryl or 5- or 6-memberedheteroarylC₁₋₃alkyl and R^(d) is hydrogen or C₁₋₆alkyl, wherein alkyl,alkenyl, alkynyl, phenyl and heteroaryl groups are optionallysubstituted. Examples of substituents include those mentioned above forring A. In particular hydroxy.

[0043] When an alkenyl or alkynyl group is directly linked to thenitrogen of a primary or secondary amine it will be appreciated that thedouble or triple bond may not be in the 1-position. Similarly alkylgroups which are substituted by halo, hydroxy or an amine may not besubstituted by these substituents in the 1-position when the alkyl groupis directly linked to the nitrogen of a primary or secondary amine.

[0044] Preferably A is an optionally substituted:

[0045] phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl,thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least twoadjacent ring carbon atoms;

[0046] More preferably A is optionally substituted:

[0047] phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.

[0048] Most preferably A is optionally substituted: phenyl or thienyl.

[0049] In particular A is optionally substituted phenyl.

[0050] Preferably B is optionally substituted:

[0051] pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, thiadiazolyl,imidazolyl, pyrazinyl, pyrimidyl, or oxazolyl.

[0052] More preferably B is optionally substituted:

[0053] pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.

[0054] Yet more preferably B is optionally substituted:

[0055] pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.

[0056] Yet more preferably B is optionally substituted:

[0057] phenyl, pyridyl or pyridazinyl.

[0058] Most preferably B is pyridazinyl.

[0059] Preferably D is optionally substituted: pyridyl, thienyl,thiazolyl, furyl or phenyl.

[0060] More preferably D is optionally substituted: thienyl, furyl orphenyl.

[0061] Most preferably D is optionally substituted phenyl.

[0062] Preferred optional substituents for ring carbon atoms in A, arehalo, nitro, trifluoromethyl, cyano, amino, C₁₋₆alkoxy, carbamoyl,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₅₋₇cycloalkenylC₂₋₃alkenyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄alkyl)carbamoyl,C₁₋₄alkanoylamino, S(O)_(p)C₁₋₆alkyl, C₁₋₄alkanesulphonamido,benzenesulphonamido, C₁₋₆alkanoyl, C₁₋₄alkoxyiminoC₁₋₄alkyl andhydroxyiminoC₁₋₄alkyl.

[0063] Most preferred optional substituents for ring carbon atoms in Aare chloro, bromo and methanesulphonyl.

[0064] In particular A is substituted on a ring carbon atom by bromo.

[0065] Preferably, when A is a 6-membered ring, A is unsubstituted orsubstituted in the 4-position relative to the —X— linking group.Preferred optional substituents for ring carbon atoms of B are halo,amino, diC₁₋₄alkylamino, C₁₋₄alkylamino, trifluoromethyl, nitro,hydroxy, methyl, C₁₋₄alkyl, C₁₋₄alkoxy and cyano.

[0066] More preferred optional substituents for ring carbon atoms of Bare fluoro, chloro, bromo, trifluoromethyl, hydroxy, methyl, methoxy andcyano.

[0067] Preferably D is optionally substituted by 1 or 2 substituentsselected from halo, trifluoromethyl, nitro, hydroxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, cyano, C₁₋₆alkoxy,—S(O)_(p)C₁₋₄alkyl (p is 0, 1 or 2), C₁₋₄alkanoyl, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl, C₃₋₇cycloalkylC₂₋₃alkenyl,C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₅₋₇cycloalkenylC₂₋₃alkenyl, wherein C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl,C₁₋₆alkyl and C₁₋₆alkyloxy are optionally substituted bytrifluoromethyl, hydroxy, halo, nitro, cyano or amino.

[0068] Most preferred optional substituents for D include halo, nitro,hydroxy, cyano, C₁₋₆alkyl, amino, C₁₋₆alkoxy or carbamoyl. Mostpreferably D is unsubstituted.

[0069] Preferably A is unsubstituted or substituted by one substituent.

[0070] Preferably B is unsubstituted or substituted by one substituent.

[0071] Preferably R¹ is carboxy, carbamoyl, tetrazolyl or of the formula—CONR^(a)R^(a1) or —CONHSO₂R^(b).

[0072] Preferably, R^(a1) is hydrogen, hydroxy or optionallysubstituted: C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, cyclopropylC₁₋₄alkyl,cyclobutylC₁₋₄alkyl, cyclopentylC₁₋₄alkyl, cyclohexylC₁₋₄alkyl,pyridylC₁₋₄alkyl, pyrimidylC₁₋₄alkyl, pyrazinylC₁₋₄alkyl,furylC₁₋₄alkyl, pyridazinylC₁₋₄alkyl, tetrazolylC₁₋₄alkyl,pyrrolidinylC₁₋₄alkyl, morpholinylC₁₋₄alkyl, imidazoliumC₁₋₄alkyl,N-methylimidazoliumC₁₋₄alkyl, pyridiniumC₁₋₄alkyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, N-methylpyrimidinium, N-methylimidazolyl,pyridinium, pyrimidinium, tetrazolyl, phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclopentenylC₁₋₄alkyl, cyclohexenylC₁₋₄alkyl or cycloheptenylC₁₋₄alkyl.

[0073] More preferably R^(a1) is hydrogen, C₁₋₆alkyl (optionallysubstituted by halo, hydroxy, nitro, cyano, amino, carboxy,C₁₋₄alkoxycarbonyl), pyridylC₁₋₄alkyl, pyrimidylC₁₋₄alkyl,pyrazinylC1-4alkyl, furylC₁₋₄alkyl, pyridazinylC₁₋₄alkyl,tetrazolylC₁₋₄alkyl, or C₂₋₆alkenyl.

[0074] Most preferably R^(a1) is C₁₋₄alkyl (optionally substituted byone or two substituents selected from hydroxy, carboxy andC₁₋₄alkoxycarbonyl), pyridylC₁₋₄alkyl and furylC₁₋₄alkyl.

[0075] Preferably —C₁₋₃alkylCONR^(a)R^(a1) is —CH₂CONR^(a)R^(a1).

[0076] Preferably —C₁₋₃alkylCONHSO₂R^(b) is —CH₂CONHSO₂R^(b).

[0077] Preferably —C₁₋₃alkylCONR^(a)NR^(c)R^(d) is—CH₂CONR^(a)NR^(c)R^(d).

[0078] Preferably R^(b) is optionally substituted: C₁₋₆alkyl,

[0079] C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₃alkyl,C₅₋₇cycloalkenylC₂₋₃alkenyl, 5- or 6-membered heteroarylC₁₋₃alkyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₃alkyl,phenylC₁₋₃alkyl, phenyl, 5- or 6-membered heteroaryl or 5- or 6-memberedsaturated or partially saturated heterocyclyl.

[0080] More preferably R^(b) is C₁₋₄alkyl (optionally substituted byhydroxy, nitro, cyano, amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino,C₁₋₄alkanoylamino, C₁₋₄alkyl-N—C₁₋₄alkanoylamino, carbamoyl,C₁₋₄alkylcarbamoyl, di-C₁₋₄alkanoylcarbamoyl, halo, C₁₋₄alkoxy) oroptionally substituted phenylC₁₋₃alkyl, pyridylC₁₋₃alkyl, phenyl,thienyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl or1,1-dioxidotetrahydrothienyl.

[0081] Most preferably R^(b) is C₁₋₄alkyl, hydroxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, phenyl (optionally substituted by halo, cyano,nitro, carbamoyl, C₁₋₄alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, hydroxy,amino, C₁₋₄alkanoylamino, N—C₁₋₄alkanoyl-N—C₁₋₄alkylamino,C₁₋₄alkylamino or di-(C₁₋₄alkyl)amino), benzyl (optionally substitutedby halo, cyano, nitro, carbamoyl, C₁₋₄alkylcarbamoyl,di-C₁₋₄alkylcarbamoyl, hydroxy, amino, C₁₋₄alkanoylamino,N—C₁₋₄alkanoyl-N—C₁₋₄alkylamino, C₁₋₄alkylamino or di-(C₁₋₄alkyl)amino),thiadiazolyl (optionally substituted by C₁₋₄alkanoylamino, amino,C₁₋₄alkylamino or di-C₁₋₄alkylamino), thienyl (optionally substitued byhalo or pyridyl), isoxazolyl (optionally substituted by C₁₋₄alkyl orhalo), pyrazolyl (optionally substituted by C₁₋₄alkyl or halo) or1,1-dioxidotetrahydro-2-thienyl.

[0082] Preferably R^(c) is hydrogen and R^(d) is 5- or 6-memberedheteroaryl or R^(c) and R^(d), together with the nitrogen atom to whichthey are attached, form a 5- or 6-membered saturated or partiallysaturated heterocyclic ring.

[0083] More preferably R^(c) is hydrogen and R^(d) is pyridyl or R^(c)and R^(d), together with the nitrogen atom to which they are attached,form morpholino.

[0084] Preferably R¹ is carboxy, carbamoyl, tetrazolyl or of the formula—CONR^(a)R^(a1) or —CONHSO₂R^(b).

[0085] Most preferably R¹ is carboxy.

[0086] More preferably R² is hydrogen, methyl, ethyl, cyclopropylmethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl,allyl or 2-propynyl.

[0087] Most preferably R² is hydrogen, ethyl, allyl or 2-propynyl.

[0088] In particular R² is hydrogen or ethyl.

[0089] Preferably R³ is hydrogen, methyl or ethyl.

[0090] Most preferably R³ is hydrogen.

[0091] R³, is R³ with the proviso that R^(3a) is not hydrogen.

[0092] Most preferably R⁴ is hydrogen.

[0093] In one aspect A is optionally substituted: naphthyl, pyridyl,pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl,thiadiazolyl having at least two adjacent ring carbon atoms or abicyclic ring system of the formula:

[0094] wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphur oroxygen and H is nitrogen or CH.

[0095] In another aspect A is optionally substituted phenyl.

[0096] Preferably m is 2.

[0097] In one aspect P¹ is oxygen.

[0098] In another aspect P¹ is sulphur.

[0099] Preferably R⁴ is hydrogen, methyl or ethyl.

[0100] Most preferably R⁴ is hydrogen.

[0101] When —Z— is —CH(R³)P¹—, —CH(R³)CH(R³)N(R²)— or —N(R²)CH(R³)—,

[0102] —X— is preferably —OCH₂—.

[0103] When —Z— is —[CH(R³)]m—, —X— is preferably —CH₂CH₂— or —NHCH₂—.

[0104] When —Z— is —CH(R³)N(R²)—, —X— is preferably —CH₂CH₂—, —CH₂—, —O—or —NHCH₂—.

[0105] A preferred class of compounds is that of the formula (II):

[0106] wherein

[0107] Z, X, R¹ and R² are as hereinabove defined, n is 0 or 1, R⁵ ishydrogen or as hereinabove defined for substituents for ring carbonatoms in D, R⁶ is hydrogen or as hereinabove defined for substituentsfor ring carbon atoms in A and B is phenyl, thienyl, pyridazinyl,pyridyl, or thiazolyl.

[0108] It is to be understood that, insofar as certain of the compoundsof formula (I) defined above may exist in optically active or racemicforms, by virtue of the compounds of the formula (I) containing anasymmetric carbon atom, the invention includes in its definition ofactive ingredient any such optically active or racemic form whichpossesses pain relieving properties. The synthesis of optically activeforms may be carried out by standard techniques of organic chemistrywell known in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form. Similarly, painrelieving properties may be evaluated using the standard laboratorytechniques referred to hereinafter.

[0109] An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy group is, for example, a pharmaceutically acceptableester which is hydrolysed in the human or animal body to produce theparent acid, for example, a pharmaceutically acceptable ester formedwith a (1-6C)alcohol such as methanol, ethanol, ethylene glycol,propanol or butanol, or with a phenol or benzyl alcohol such as phenolor benzyl alcohol or a substituted phenol or benzyl alcohol wherein thesubstituent is, for example, a halo (such as fluoro or chloro),(1-4C)alkyl (such as methyl) or (1-4C)alkoxy (such as ethoxy) group. Theterm also includes α-acyloxyalkyl esters and related compounds whichbreakdown to give the parent hydroxy group. Examples of α-acyloxyalkylesters include acetoxymethoxycarbonyl and2,2-dimethylpropionyloxymethoxycarbonyl. An in vivo hydrolysable esterof a compound of the formula (I) containing a hydroxy group is, forexample, a pharmaceutically acceptable ester which is hydrolysed in thehuman or animal body to produce the parent alcohol. The term includesinorganic esters such as phosphate esters and α-acyloxyalkyl ethers andrelated compounds which as a result of the in vivo hydrolysis of theester breakdown to give the parent hydroxy group. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

[0110] A suitable value for an in vivo hydrolysable amide of a compoundof the formula I containing a carboxy group is, for example, aN-(1-6C)alkyl or N,N-di-(1-6C)alkyl amide such as N-methyl, N-ethyl,N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

[0111] A suitable pharmaceutically-acceptable salt of a compound of theformula (I) is, for example, an acid-addition salt of a compound of theformula (I) which is sufficiently basic, for example an acid-additionsalt with an inorganic or organic acid such as hydrochloric,hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, forexample a salt of a compound of the formula (I) which is sufficientlyacidic, for example an alkali or alkaline earth metal salt such as acalcium or magnesium salt, or an ammonium salt, or a salt with anorganic base such as methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0112] In a further aspect the invention provides a process forpreparing compounds of the formula (I) or pharmaceutically acceptablesalts or in vivo hydrolysable amides or ester thereof, which comprisesdeprotecting a compound of the formula (III):

[0113] wherein R⁷ is R¹ or protected R¹, —Z¹— is —Z— or protected —Z—,R², R³, Z, X, A, B and D are as hereinabove defined, and any optionalsubstituents are optionally protected and at least one protecting groupis present;

[0114] and thereafter if necessary;

[0115] i) forming a pharmaceutically acceptable salt;

[0116] ii) forming an in vivo hydrolysable ester or amide;

[0117] iii) converting one optional substituent into another optionalsubstituent.

[0118] Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question, and may beintroduced by conventional methods.

[0119] Protecting groups may be removed by any convenient method asdescribed in the literature or known to the skilled chemist asappropriate for the removal of the protecting group in question, suchmethods being chosen so as to effect removal of the protecting groupwith minimum disturbance of groups elsewhere in the molecule.

[0120] A suitable protecting group for a hydroxy group is, for example,an arylmethyl group (especially benzyl), a tri-(1-4C)alkylsilyl group(especially trimethylsilyl or tert-butyldimethylsilyl), anaryldi-(1-4C)alkylsilyl group (especially dimethylphenylsilyl), adiaryl-(1-4C)alkylsilyl group (especially tert-butyldiphenylsilyl), a(1-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especiallyallyl), a (1-4C)alkoxymethyl group (especially allyl), a(1-4C)alkoxymethyl group (especially methoxymethyl) or atetrahydropyranyl group (especially tetrahydropyran-2-yl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.Alternatively a trialkylsilyl or an aryldialkylsilyl group such as atert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed,for example, by treatment with a suitable acid such as hydrochloric,sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metalor ammonium fluoride such as sodium fluoride or, preferably,tetrabutylammonium fluoride. Alternatively an alkyl group may beremoved, for example, by treatment with an alkali metal(1-4C)alkylsulphide such as sodium thioethoxide or, for example, bytreatment with an alkali metal diarylphosphide such as lithiumdiphenylphosphide or, for example, by treatment with a boron oraluminium trihalide such as boron tribromide. Alternatively a(1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric ortrifluoroacetic acid.

[0121] Alternatively a suitable protecting group for a hydroxy group is,for example, an acyl group, for example a (2-4C)alkanoyl group(especially acetyl) or an aroyl group (especially benzoyl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide.

[0122] A suitable protecting group for an amino, imino or alkylaminogroup is, for example, an acyl group, for example a (2-4C)alkanoyl group(especially acetyl), a (1-4C)alkoxycarbonyl group (especiallymethoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), anarylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroylgroup (especially benzoyl). The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl oraroyl group may be removed for example, by hydrolysis with a suitablebase such as an alkali metal hydroxide, for example lithium or sodiumhydroxide. Alternatively an acyl group such as a tert-butoxycarbonylgroup may be removed, for example, by treatment with a suitable acidsuch as hydrochloric, sulphuric or phosphoric acid or trifluoroaceticacid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl groupmay be removed, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

[0123] A suitable protecting group for a carboxy group is, for example,an esterifying group, for example a (1-4C)alkyl group (especially methylor ethyl) which may be removed, for example, by hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium orsodium hydroxide; or, for example, a tert-butyl group which may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.

[0124] In another aspect the compounds of the formula (I) or (III) maybe prepared by:

[0125] a) when —Z¹— is —CH(R³)NHCH(R³)—, —CH(R³)CH(R³)NH—, —CH(R³)NH— or—NHCH(R³)— reducing a compound of the formula (IVa) or (IVb):

[0126] b) when —Z¹— is —CH(R³)N(R⁸)CHR³), —CH(R³)CH(R³)N(R⁸)— or—CH(R³)N(R⁹)— and B is an activated heterocycle and R⁸ is hydrogen orC₁₋₆alkyl, reacting a compound of the formula (V) with a compound of theformula (VI):

[0127] c) converting R¹⁰ to R⁷ in a compound of the formula (VII):

[0128] d) when —Z¹— is —CH(R³)N(R⁸)—, —N(R⁸)CH(R³)— or—CH(R³)CH(R³)N(R⁸)— and R⁸ is other than hydrogen, reacting a compoundof the formula R⁸X² with a compound of the formula (VIII):

[0129] e) when —Z¹— is —CH(R³)N(R⁸)CH(R³)—, —CH(R³)CH(R³)N(R⁸)— or—CH(R³)N(R⁸)—, reacting a compound of the formula (IX) with a compoundof the formula (X):

[0130] f) when X is —CH₂CH₂—, reducing a compound of the formula (XIA)or (XEB):

[0131] g) when X is —CH₂—, hydrogenating a compound of the formula(XII):

[0132] h) when X is —CH₂—, reacting a compound of the formula (XIII)with a compound of the formula X³⁻D

[0133] i) when X is —O—, reacting a compound of the formula (XIV) with acompound of the formula X⁵-D:

[0134] j) when X is —NHCH₂—, reacting a compound the formula (XV) with acompound of the formula X⁷CH₂D or D-CHO:

[0135] k) when X is —OCH₂—, reacting a compound of the formula L¹-CH₂Dwith a compound of the formula (XVI):

[0136] l) when X is —N(R⁴)CH₂—, reacting a compound of the formula(XVII) with a compound of the formula R⁴X⁸:

[0137] m) when —Z¹— is of the formula —CH(R³)CH₂N(R⁸)—, reducing acompound of the formula (XVIII)

[0138] n) when —Z¹— is of the formula —[CH(R³)]m—, by reducing acompound of the formula (XIXa) or (XIXb):

[0139] o) when —Z¹— is of the formula —[CH(R³)]m—, and m is 3, byreducing a compound of the formula (XX):

[0140] p) when —Z¹— is of the formula —[CH(R³)]m—, and B is an activatedheterocycle by reacting a compound of the formula (XXI) with a compoundof the formula (XXII):

[0141] q) when —Z¹— is of the formula —CH(R³)P¹—, reacting a compound ofthe formula HP¹—B—R⁷ with a compound of the formula (XXIII):

[0142] r) when —Z¹— is of the formula —CH(R³)P¹—, reacting a compound ofthe formula X¹⁴—B—R⁷ with a compound of the formula (XXIV):

[0143] s) when —Z¹— is of the formula —N(R⁸)CH(R³)—, reacting a compoundof the formula (XXV) with a compound of the formula (VI):

[0144] wherein R³, R⁷, Z¹, A, B, D and X as hereinabove defined, R⁸ isR² or protected R², X¹ is a leaving group, R¹⁰ is a precursor of R⁷, X²is a leaving group, R¹¹ is a removable activating group, R¹² is aleaving group, either X³ is a leaving group and X⁴ is ZnX³ or X⁴ is aleaving group and X³ is ZnX⁴, either X⁵ is a leaving group and X⁶ ishydroxy or X⁶ is hydroxy and X⁵ is a leaving group, L¹, X⁷ X⁸, X⁹, X¹³and X¹⁴ are leaving groups and p and q are independently 0 or I providedthat p and q are not both 1; and thereafter if necessary:

[0145] i) removing any protecting groups;

[0146] ii) forming a pharmaceutically acceptable salt;

[0147] iii) forming an in vivo hydrolysable ester or amide;

[0148] iv) converting an optional substituent into another optionalsubstituent.

[0149] Particular values for leaving groups include halogen, forexample, chloro, bromo and iodo, sulphonates, for example tosylate,p-bromobenzenesulphonate, p-nitrobenzenesulphonate, fluorosulphonate,methanesulphonate and triflate or phosphoric esters such as adiarylphosphoric ester.

[0150] Compounds of the formula (IVa) and (IVb) can be reduced usingagents such as odium borohydride or sodium cyanoborohydride. Thecompounds of the formula (IVa) may be prepared by reacting a compound ofthe formula (X) with a compound of the formula (XVa1)

[0151] wherein A, X, D and p are as hereinabove defined.

[0152] The reaction between compounds of the formulae (X) and (IVa1) maybe carried out under standard conditions known in the art for theformation an imine (Schiffs base), which can be reduced in situ. Forexample imine formation and reduction in situ may be carried out in aninert solvent such as toluene or tetrahydrofuran, in the presence of areducing agent such as sodium cyanoborohydride (NaCNBH₃) under acidicconditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201,1979). When p is 1 and R³ is hydrogen, compounds of the formula (IVa1)may be prepared by reducing a compound of the formula (XVIIIA)—seescheme 1.

[0153] The compounds of the formula (IVb) may be formed by reacting acompound of the formula R⁷—B—C(═O)R³ with a compound of the formula(IVb1)

[0154] and reducing the product in situ, wherein A, D and X are ashereinabove defined.

[0155] The reaction between compounds of the formulae R⁷—B—C(═O)—R³ and(IVb1) is normally carried out as reductive alkylation. In this reactionthe compound of the formula (IVb1) is reduced to the related amine,which reacts with the compound of the formula R⁷—B—C(═O)—R³ to give acompound of the formula (IVb) which is immediately reduced to a compoundof the formula (I) or (III) in situ. Alternatively one or more stepscould be performed separately. Palladium-on-carbon is commonly used asthe reducing agent in this reaction.

[0156] Compounds of the formulae (V) and (VI) may be reacted togetherunder standard conditions for example, in an aprotic solvent such as DMFin the presence of a weak base, in a temperature range of ambient to180° C. Suitable bases include sodium hydrogen carbonate and amide basessuch as Hunig's base, N-ethyl-N,N-diisopropylamine, tributylamine or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable values for X¹include, halo, tosylate, mesylate and triflate. In particular X¹ ischloro or bromo.

[0157] In general this process is best used when ring B is an electronpoor heterocycle such as pyridine, pyrimidine, pyridazine or pyrazine.

[0158] Compounds of the formula (V) wherein p is 1 are convenientlyprepared from compounds of the formula (VA) as shown in scheme 1.Compounds of the formula (VB) in which X¹⁵ is a leaving group, such asbromo, are reacted with a cyanide salt such as potassium cyanide in asolvent such as DMF, in a temperature range of 20-140° C. to give acompound of the formula (VC). 18 Crown 6 may be added as a catalyst. Thecompound of the formula (VC) may be reduced by catalytic hydrogenationwith, for example, palladium on carbon, borane.THF, borane.DMScomplexes, lithium aluminium hydride or lithiumborohydide/trimethylsilyl chloride to give a compound of the formula(VA). Alternatively, a compound of the formula (VD) may be prepared byreacting the compound of the formula (VE) with CH₃NO₂ in the Henryreaction. The reaction is performed in the presence of an amine basesuch as triethylamine, in THF or CH₃NO₂ as solvent, in a temperaturerange of 0-20° C. The compound of the formula (VD) may then be reducedwith a strong reducing reagent such as lithium aluminium hydride or byhydrogenation with palladium-on-carbon as the catalyst, to give acompound of the formula (VA). When R⁸ is other than hydrogen, compoundsof the formula (V) may be prepared by alkylating the compound of theformula (VA) using a similar reaction to that described in process d).

[0159] Particular values for R¹⁰ include cyano, carbamoyl,alkoxycarbonyl, carboxy and activated carboxy groups such as acidchlorides and activated esters.

[0160] The cyano group may be converted into a tetrazole ring byreacting it with, for example, ammonium or tin azide in an aproticsolvent such as DMF, in a temperature range of 100° C. to 130° C. Forfurther information on tetrazole synthesis see S. J. Wittenberger and B.J. Donner JOC, 1993, 58, 4139-4141; BE Huff et al, Tet. Lett, 1993, 50,8011-8014; and J. V. Duncia et al, JOC 1991, 56, 2395-2400.

[0161] Alkoxycarbonyl may be converted into a carboxy group by acid orbase hydrolysis. For example, base hydrolysis may be carried out in anorganic solvent such as methanol or THF in a temperature range ofambient to 100° C., in the presence of sodium hydroxide or potassiumhydroxide.

[0162] Acid hydrolysis may, for example, be carried out in neat formicacid or neat trifluoroacetic acid optionally in an organic solvent suchas dichloromethane.

[0163] An alkoxycarbonyl or an activated carboxy group, such as an acidchloride or activated ester, or an acyl group such as an alkanoyl groupmay be converted to an amide group by reacting it with the appropriateamine in an inert solvent such as DMF or dichloromethane, in atemperature range of 0° C. to 150° C., preferably around ambienttemperature, in the presence of a base such as triethylamine.

[0164] The compounds of the formulae (VIII) and R⁸X² may be reactedtogether in an aprotic solvent such as DMF in the presence of a basesuch as sodium carbonate or sodium hydride. Suitable values for X² arehalo, tosylate, mesylate and triflate, in particular halo such as iodo.

[0165] The reaction between compounds of the formulae (IX) and (X) isconveniently carried out under mild conditions known for the Mitsunobureaction (Mitsunobu, O. Synthesis 1981, 1), for example in the presenceof di (C₁₋₄alkyl)azocarboxylate and triphenylphosphine or1¹,1¹-(azodicarbonyl)dipiperidine and tributylphosphine (Tet. Lett. 34,1993, 1639-1642) in an inert solvent such as toluene, benzene,tetrahydrofuran or diethylether, in particular toluene. Examples ofremovable activating groups are tert-butyloxycarbonyl andtrifluoroacetyl.

[0166] Furthermore the alkoxycarbonyl groups can be removed byhydrolysis of the ester to leave the unprotected amino group andtrifluoroacetyl groups can be reduced to 2,2,2-trifluoroethyl.

[0167] When R⁸ is alkoxycarbonyl and R¹² a leaving group such astosylate, mesylate, chloro, bromo or iodo, the compounds of the formula(IX) and (X) can be reacted together to form a compound of the formula(I) or (III), in the presence of a strong base such as sodium hydride,potassium hydride, potassium tert-butoxide, lithium diisopropyl amine orLiN(SiMe₃)₂, in DMF or an etherial solvent such as diethyl ether or THF,in a temperature range of −78° C. to ambient temperature.

[0168] Compounds of the formula (IX) wherein p is 1 are convenientlyprepared from a compound of the formula (IXA)—see scheme 1. For exampleby reacting the compound of the formula (IXA) with tosyl or mesylchloride or using Mitsunobu reagents. Compounds of the formula (IXA) maybe formed as shown in scheme 1, from compounds of the formulae (VD) or(IXB).

[0169] Compounds of the formula (VD) may be converted to compounds ofthe formula (IXA) by either sequential treatment with Bu₃SnH, ozone andsodium borohydride, (Tet Lett (1987), 28, 53, 67) or, hydrogenation withPd/C (or other catalysts to the RCH₂CH₂NO₂) followed by the Nef reaction[conditions for the Nef reaction include aqueous TiCl₃, or 30%H₂O₂/K₂CO₃ (Nef reaction is detailed in March, Advanced OrganicChemistry)] and sodium borohydride reduction, to give the aldehyde(RCH₂CHO).

[0170] Compounds of the formula (IXB) are prepared by reacting acompound of the formula (IXC) with a compound of the formula CH₂═CHM,wherein M is trialkyltin, magnesium halide or di(alkoxy)borane/weak base(for example potassium or caesium carbonate) in the presence of acatalytic amount of palladium (0). The magnesium and tin reactions areconveniently performed in anhydrous THF. The compound of the formula(IXB) is conveniently converted to the alcohol (IXA) by reacting it withcatechol borane followed by treatment with hydrogen peroxide.

[0171] Compounds of the formula (X) are conveniently prepared fromcompounds of the formula H₂N—(CH(R³))_(q)—B—R⁷ wherein B and R⁷ are ashereinabove defined. R⁸ may be introduced using a similar reaction tothat of process d) and R¹¹ may be introduced by standard methods knownin the amino-protecting group art.

[0172] Compounds of the formula NH₂(CH(R³))_(q)—B—R⁷ are generally knownin the art or an be prepared from related compounds having otherfunctional groups in place of the amino group. For example, a compoundof the formula NO₂(CH(R³))_(q)—B—R⁷ may be reduced to the amino group.

[0173] The compounds of the formula (XIa) and (XIb) may be reduced understandard conditions known in the art for the reduction of olefins, andacetylenes, for example, catalytic hydrogenation using Raney nickel,platinum metal or its oxide, rhodium, zinc oxide, palladium-on-charcoalor Wilkinson's catalyst [RhCl(Ph₃P)₃] as the catalyst. When halo groupsare present in the compounds of the formula (XIa) or (XIb), Wilkinson'scatalyst is preferred.

[0174] Catalyst hydrogenation is conveniently carried out in thetemperature range 0° C. to 150° C., but preferably at ambienttemperature at slightly above atmospheric pressure, unless the doublebond is highly substituted in which case higher temperatures andpressure may be required, or Wilkinson's catalyst in which case atemperature of approximately 50° C. and pressure of approximately 50atmospheres are preferable.

[0175] Compounds of the formula (XIa) can be prepared using a Wittig orHorner-Emmons reagent. For example, compounds of the formula (XIa1) and(XIa2) may be reacted together in an inert solvent such as hexane,tetrahydrofuran or diethyl ether in a temperature range of −78° C. toambient.

[0176] wherein R¹³—R¹⁵ are independently C₁₋₆alkyl or optionallysubstituted phenyl.

[0177] Preferably R¹³—R¹⁵ are all the same. In particular R¹³—R¹⁵ areall phenyl.

[0178] The compounds of the formula (XIa2) are rarely isolatable andusually prepared in situ by deprotonating a compound of the formula(XIa3) (scheme 2). Deprotonation is usually carried out in an inertsolvent such as tetrahydrofuran or diethyl ether, in a temperature rangeof −78° C. to ambient, in the presence of a strong base. Examples ofstrong bases are lithium hexamethyldisilylamide, CH₃SOCH₂—Na⁺ and butyllithium.

[0179] Compounds of the formula (XIa3) may be prepared by reacting acompound of the formula (XIa4) with a compound of the formula (XIa5)(scheme 2). Suitable values for L¹¹ include halogen, such as chloro,bromo or iodo. Typically an inert solvent such as acetonitrile, diethylether, tetrahydrofuran or toluene is used and a temperature range of 50°C. or 120° C. The compounds of the formula (XIa4) may be known orprepared from another compound of the formula (XIa4) or a compound ofthe formula D—CHO wherein D is as hereinabove defined. For example thecompound of the formula D—CHO may be reduced to a compound of theformula (XIa4) wherein L¹¹ is hydroxy. A compound of the formula (XIa4),wherein L¹¹ is hydroxy, may then be converted to a compound of theformula (XIa4) wherein L¹¹ is bromo by, for example, bromonating withtetrabromomethane/triphenylphosphine or tribromophosphine.

[0180] wherein D, R¹³—R¹⁵ and L¹¹ are as hereinabove defined.

[0181] Alternatively, compounds of the formula (XIa) can be prepared bydehydrating a compound related to a compound of the formula (I) or (III)in which X is —CH(OH)CH₂—. Dehydration is conveniently carried out usingstandard methods known in the art, for example, at elevated temperaturesin the presence of sulphuric acid, phosphoric acid or aluminium oxide.Alternatively, the hydroxy group may be converted to a bromo group. Thealkene can then be formed by treatment with a strong base such as sodiumhydride or LDA.

[0182] The compounds in which X is —CH(OH)CH₂— may be prepared byreacting a compound of the formula (XIa1) with D—CH₂— in the form of azinc or Grignard reagent. Reaction conditions for these common reactionsare known in the art. For example by reacting DCH₂X⁸, wherein X⁸ is aleaving group such as bromo or iodo, with zinc or magnesium asappropriate in an inert solvent such as ether or THF, in a temperaturerange of 0° C. to reflux. The reaction can be initiated by theintroduction of iodine or 1,2-dibromomethane if necessary. When estergroups are present in one or other of the reagents, the zinc reaction ispreferred.

[0183] Compounds of the formula (XIb) are conveniently prepared byreacting a compound of the formula (XIb1) with a D—X⁷Cu(I) salt, whereinX⁷ is a leaving group under conditions known for the Heck reaction:

[0184] The reaction is performed in the presence of palladium(0)catalyst, such as Pd(PPh₃)₄ or Pd(OAc)₂ which form the active Pd(0)catalyst in situ. Other palladium(0) catalysts are known in the art.Suitable leaving groups may be chosen from bromo, chloro, iodo,trifluoromethylsulphonyloxy or fluorosulphonate.

[0185] Compounds of the formula (XIb1) can be formed by reacting acompound of the formula (XIb2) with a compound of the formula CH≡C—TMSor CH≡CC(Me)₂OH:

[0186] wherein TMS is trimethylsilyl and X¹⁰ is a leaving group. Thiscoupling reaction is performed in an inert solvent, such asdimethylformamide, tetrahydrofuran or NMP, in the presence ofpalladium(0), copper (I) in the form of a salt such as the halide ortriflate, and a base such as triethylamine, tributylamine,1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium acetate.

[0187] It is not always convenient to form the acetylene lower link inintermediates containing the upper —Z¹—B—R⁷ group, because certaingroups may be sensitive to the reaction conditions. It may therefore bemore appropriate to form the acetylene link prior to the introduction ofthe upper link using processes and intermediates related to those ofprocesses a), b), e), m), n), o), p), q), or r) and their precursorprocesses.

[0188] The hydrogenation of the compound of the formulae (XII) isperformed under standard conditions known in the art. Examples of thecatalytic hydrogenation agents are given above in the discussion of thereduction of compounds of the formula (XIa) and (XIb).

[0189] Compounds of the formula (XII) may be formed by reacting acompound of the formula D—CHO or

[0190] with the appropriate zinc or Grignard reagent [R⁷—Z⁷—A⁻ and D⁻respectively] under conditions known in the art for these reactions.

[0191] Compounds of the formulae (XIII) and X³-D are convenientlyreacted together in a polar aprotic solvent such as dimethylformamide,tetrahydrofuran or NMP in the presence of palladium(0) or nickel(O) ascatalyst.

[0192] The reaction between the compound of the formula (XIV) and thecompound of the formula X⁵-D is conveniently a copper mediatedoxygen-arylation reaction. The reaction is carried out in an inertsolvent such as dimethylformamide or N-methylpyrrolidone (NMP) in thepresent of a Cu(1)X⁶ salt and a weak base such as potassium carbonate orcaesium carbonate. The reaction is normally carried out in thetemperature range of 80-250° C. Preferably the leaving group is iodo orbromo.

[0193] Compounds of the formulae (XV) and X⁷CH₂D are reacted together inthe presence of a base under similar reaction conditions to thosedescribed above for the reaction between compounds of the formulae (V)and (VI). Preferably X⁷ is bromo. Compounds of the formulae (XV) andD—CHO are conveniently reacted together in an alcohol such as ethanol orisopropanol, in the presence of NaCNBH₃ and acetic acid or,alternatively, hydrogenated in the presence of palladium-on-carbon.

[0194] Compounds of the formula (XV) may be prepared by reducing therelated nitro compound.

[0195] The ether-forming reaction between compounds of the formulaeL¹—CH₂D and (XVI) is typically performed in an inert solvent such asacetone or DMF, in a temperature range of ambient to 60° C., in thepresence of a mild base. Suitable values for L¹ include tosylate,mesylate, triflate and halo, for example chloro or bromo. When L¹ isbromo, the reaction may, for example, be performed in DMF, at ambienttemperature in the presence of a base such as potassium carbonate. WhenL¹ is hydroxy, the Mitsunobu reaction may be used (O. Synthesis, 1981,1). For example performing the reaction in tetrahydrofuran or toluene inthe presence of diethyl azodicarboxylate and triphenylphosphine.

[0196] The compounds of the formula L¹—CH₂—D and (XVI) may alternativelybe reacted together using a phase transfer system.

[0197] The compounds of the formula (XVII) and R⁴X⁸ may be reactedtogether in an aprotic solvent such as DMF in the presence of a basesuch as sodium carbonate or sodium hydride. Suitable values for X⁸ arehalo, tosylate, mesylate and triflate, in particular halo such as iodo.

[0198] Compounds of the formula (XVIII) are conveniently reduced withlithium aluminium hydride or a borane, under standard conditions knownin the art. Compounds of the formula (XVIII) may be formed as shown inScheme 1. The compound of the formula (VC) is hydrolysed with an aqueousacid or base or basic peroxide, for example aqueous hydrochloric acid,sodium hydroxide or hydrogen peroxide, in a temperature range of 0 to100° C. Carboxylic acid (XVIIIA) may then be reacted with an amine ofthe formula R⁷—B—NHR⁸ to give the compound of the formula (XVIII) underconditions known in the art for the formation of amides. For examplessee pages 972-976 of ‘Larock—Comprehensive Organic Transformations’;VCH: New York, 1989:

[0199] Compounds of the formula (XIXa) are conveniently prepared byreacting together compounds of the formulae (XIXa1) and (XIXa2) underconditions known for the Wittig or Emmons-Horner reaction.

[0200] wherein p and q are independently 0 or 1, provided that p and qare not both 1.

[0201] For example, under similar conditions to those described abovefor the reaction between compounds of the formulae (XIa1) and (XIa2).

[0202] The compounds of the formula (XIXa2) are rarely isolatable andusually prepared in situ by deprotonating a compound of the formula(XIXa3) (scheme 3). Deprotonation is usually carried out as describedfor the compounds of the formula (XIa3).

[0203] Compounds of the formula (XIXa3) may be prepared by reacting acompound of the formula (XIXa4) with a compound of the formula (XIXa5)(scheme 3). Suitable values for X¹¹ include halogen, such as chloro,bromo or iodo. Typically an inert solvent such as acetonitrile, diethylether, tetrahydrofuran or toluene is used and a temperature range of 50°C. to 120° C. The compounds of the formula (XIXa4) may be known orprepared from another compound of the formula (XIXa4) or a compound ofthe formula (XIXa6):

[0204] wherein B, R³, R⁷ and q are as hereinabove defined. For examplethe compound of the formula (XIXa6) may be reduced to a compound of theformula (XIXa4) wherein X¹¹ is hydroxy. A compound of the formula(XIXa4), wherein X¹¹ is hydroxy, may then be converted to a compound ofthe formula (XIXa4) wherein X¹¹ is bromo by, for example, bromonatingwith tetrabromomethane/triphenylphosphine or tribromophosphine.

[0205] wherein B, R³, R⁷, R^(13—)R¹⁵, p, q and X¹¹ are as hereinabovedefined.

[0206] Alternatively compounds of the formula (XIXa) can be prepared bydehydrating a compound of the formula (XIXa7).

[0207] wherein A, B, D, X, p, q, R³ and R⁷ are as hereinabove defined.Dehydration is conveniently carried out using standard methods known inthe art, for example, at elevated temperatures in the presence ofsulphuric acid, phosphoric acid or aluminium oxide. Alternatively, thehydroxy group may be converted to a better leaving group, such astosylate which can then be converted to bromo. The alkene can then beformed by treatment with a strong base such as sodium hydride or LDA.

[0208] Compounds of the formula (XIXa7) can be prepared by reactingtogether compounds of the formula R⁷—B—[CH(R³)]_(q) CH(R³) in the formof a zinc or Grignard reagent and (XIXa8).

[0209] Standard conditions for the preparation of zinc or Grignardreagents are known in the art.

[0210] Compounds of the formula (XIXb) may be prepared by reacting aR⁷—B—X¹² Cu(I) salt with a compound of the formula (XIXb1):

[0211] under conditions described above for the ‘Heck reaction’, whereinD, R³ and A are as hereinabove defined and p is 0 or 1 and X¹² is aleaving group.

[0212] Compounds of the formula (XIXb1) may be prepared by reactingtogether compounds of the formulae TMS—C≡CH or CH≡CC(Me)₂OH and (XIXb2):

[0213] wherein A, D, X, R³, X¹⁵ and p are as hereinabove defined, underHeck conditions. For example, by performing the reaction in an inertsolvent, such as dimethylformamide, tetrahydrofuran or NMP, in thepresence of palladium (0), copper (I) in the form of a salt such as thehalide or triflate, and a base such as triethylamine, tributylamine,1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium acetate.

[0214] Compounds of the formula (XX) are reduced by standard methodsknown in the art for the reduction of α,β-unsaturated ketones, withoutaffecting ring B. For example, the double bond may be hydrogenatedcatalytically using Wilkinson's catalyst and then the ketone groupreduced, if appropriate, by forming the tosyl hydrazone and reducingwith sodium borohydride.

[0215] The compounds of the formula (XX) are conveniently prepared byreacting a compound of the formula (XXA) with a compound of the formula(XXB):

[0216] The reaction between the compounds of the formula (XXA) and (XXB)is conveniently carried out in the presence of a base, for example,lithium hydroxide or potassium tert-butoxide in an organic solvent suchas alcohol, for example, methanol.

[0217] The reaction between the compounds of the formulae (XXI) and(XXII) is conveniently performed under standard conditions known in theart. Suitable leaving groups include halo, for example, chloro, bromo oriodo, and tosylate and mesylate.

[0218] In general the reaction is performed in an inert solvent such ashexane, tetrahydrofuran or ethyl ether, in a temperature range of −100°C. to ambient temperature, in the presence of a strong base such asbutyl lithium, sec-butyl lithium, tert-butyl lithium, lithiumdiisopropylamide (LDA) or lithium hexamethyldisilylamide, preferably inthe presence of a hindered base such as LDA or lithiumhexamethyldisilylazide. For example wherein the leaving group is bromo,in in the presence of LDA at 30° C.

[0219] Compounds of the formula HP¹—B—R⁷ and (XXIII) are convenientlyreacted together in the presence of a base in a dipolar aprotic solventsuch as DMF. When the Mitsunobu reaction is used, no base is necessary.Otherwise the reaction is conveniently performed in the presence of abase. For example when P is sulphur, a suitable base is potassiumcarbonate and when P is oxygen, a suitable base is sodium hydride.

[0220] Suitable values for X¹³ include halo, tosylate, mesylate orhydroxy activated with triphenylphosphine/diethylazodicarboxylate orother Mitsunobu reagents.

[0221] The compound of the formula (XXIII) can be prepared from therelated compound in which X¹³ is hydroxy. For example by reacting thehydroxy compound with tosyl or mesyl chloride in the presence of a basesuch as triethylamine.

[0222] The reaction between compounds of the formulae X¹⁴—B—R⁷ and(XXIV) is conveniently carried out in an inert polar aprotic solventsuch as dimethylformamide or NMP in a temperature range of 80-210° C.

[0223] Suitable values for X¹⁴ include halo and tosyl.

[0224] When P is sulphur, the compound of the formula (XXIV), can beprepared by reacting a compound of the formula (XXIII) with sodiumsulphide in the presence of zinc/hydrochloric acid,triphenylphosphine/water or aqueous base in a temperature range of20-100° C.

[0225] The compounds of the formulae (XXIII), (XXIII) in which X¹³ ishydroxy and (XXIV) can be prepared using processes for the formation ofthe lower linking group —X— as described hereinabove, from appropriatestarting materials.

[0226] The reaction between compounds of the formulae (XXV) and (VI) isconveniently carried out under mild conditions known for the Mitsunobureaction (Mitsunobu, O. Synthesis 1981, 1), for example in the presenceof di (C₁₋₄alkyl)azocarboxylate and triphenylphosphine or1¹,1¹-(azodicarbonyl)dipiperidine and tributylphosphine (Tet. Lett. 34,1993, 1639-1642) in an inert solvent such as toluene, benzene,tetrahydrofuran or diethylether, in particular toluene. Examples ofremovable activating groups are tert-butyloxycarbonyl andtrifluoroacetyl.

[0227] Furthermore the alkoxycarbonyl groups can be removed byhydrolysis of the ester to leave the unprotected amino group andtrifluoroacetyl groups reduced to 2,2,2-trifluoroethyl.

[0228] When R⁸ is alkoxycarbonyl and X¹ a leaving group such astosylate, mesylate, chloro, bromo or iodo, the compounds of the formula(XXV) and (VI) can be reacted together to form a compound of the formula(I) or (I), in the presence of a strong base such as sodium hydride,potassium hydride, potassium tert-butoxide, lithium diisopropyl amine orLiN(SiMe₃)₂, in DMF or an etherial solvent such as diethyl ether or THF,in a temperature range of −78° C. to ambient temperature.

[0229] The compounds of the formula (XXV) may be prepared as shown inScheme 4

[0230] Compounds of the formula (XXVA) can be converted to a compound ofthe formula (XXV) by reacting (XXVA) with KCNO and tert-butanol in apolar aprotic solvent such as DMF or NMP, with a catalytic amount ofpallaidum (0), in a temperature range of 80-200° C.

[0231] Compounds of the formula (XXVB) are conveniently reacted with(PhO)₂PON₃ in a temperature range of 0-20° C., followed by tert-butanolin a temperature range of 20-100° C.

[0232] Compounds of the formula (XXVC) can be reduced to the amine withreagents such as zinc/hydrochloric acid, iron/acetic acid, tin (III)chloride, titanium (IV) chloride, or by catalytic hydrogenation. Theamine can then be protected with tert-butoxycarbonyl to give a compoundof the formula (XXV).

[0233] The compounds of the formulae (IVa1), (IVb1), (V), (VA), (VB),(VE), (IXC), (XIXa1), (XIXb2), (XIXa7), (XXA), (XXI), (XXIII), (XXIV),(XXVA), (XXVB) and (XXVC) can be prepared using processes for theformation of the lower linking group —X— as described hereinabove, fromappropriate starting materials. Similarly, compounds of the formulae(XIa1), (XIa2), (XIV), (XIV), (XV) and the related nitro compound, (XIV)and the zinc or Gignard reagent used in the preparation of compounds ofthe formula (XII) can be prepared using processes for the formation ofthe —Z—B—R⁷ group as described hereinabove, from appropriate startingmaterials.

[0234] The order in which the upper and lower links are constructed willdepend upon the individual substitution patterns and the compatibilityof functional groups with the reaction conditions.

[0235] The compounds of the formula (VII) may be prepared usingprocesses a), b), d)-r) from the appropriate starting material whereinR⁷ is replaced with R¹⁰.

[0236] The compounds of the formula (VIII) or (XVII) may be prepared byusing any one of processes a), b), c), e)-r) from the appropriatestarting materials wherein R⁸ is hydrogen.

[0237] The compounds of the formulae (VI) are generally known in the artor can be made by methods analogous to or similar to those used in theexamples or those known in the art for related compounds.

[0238] It is also possible to synthesise certain intermediates and evenprotected compounds using primarly ring synthesis. Here, reference ismade to the compendium ‘The Chemistry of Heterocyclic Compounds’ E. C.Taylor and A. Weissberger (published by John Wiley & Sons) and‘Comprehensive Heterocyclic Chemistry’, A. R. Katritby and C. W. Rees(published by Pergamon Press).

[0239] Optional substituents may be converted into other optionalsubstituents. For example an alkylthio group may be oxidised to analkylsulphinyl or alkysulphonyl group, a nitro group reduced to an aminogroup, a hydroxy group alkylated to a methoxy group, or a bromo groupconverted to an alkylthio group.

[0240] Various substituents may be introduced into compounds of theformulae (I) and (III) and intermediates in the preparation of compoundsof the formulae (I) and (III), when appropriate, using standard methodsknown in the art. For example, an acyl group or alkyl to group may beintroduced into an activated benzene ring using Friedel-Craftsreactions, a formyl group by formylation with titanium tetrachloride anddichloromethyl ethyl ether, a nitro group by nitration with concentratednitric acid concentrated sulphuric acid and bromine by bromination withbromine or tetra(n-butyl)ammonium tribromide.

[0241] It will be appreciated that, in certain steps in the reactionsequence to compounds of the formula (I), it will be necessary toprotect certain functional groups in intermediates in order to preventside reactions. Deprotection may be carried out at a convenient stage inthe reaction sequence once protection is no longer required.

[0242] As stated hereinbefore compounds of the formula (I) areantagonists of the pain enhancing effects of E-type prostaglandins andof value in the relief of pain which, for example, accompaniesinflammatory conditions such as rheumatoid arthritis and osteoarthritis.Certain properties of the compounds may be demonstrated using the testprocedures set out below:

[0243] (a) an in-vitro guinea pig ileum assay which assesses theinhibitory properties of a test compound against PGE₂-inducedcontractions of the ileum; ileum was immersed in oxygenated Krebssolution containing indomethacin (4 μg/ml) and atropine (1 μM) and whichwas maintained at 37° C.; the ileum was subject to a tension of 1 g; acontrol dose response curve for PGE₂-induced contraction of the ileumwas obtained; test compound (dissolved in dimethylsulphoxide) was addedto the Krebs solution and a dose response curve for the PGE₂-inducedcontraction of the ileum in the presence of the test compound wasobtained; the pA₂ value for the test compound was calculated;

[0244] (b) an in-vivo assay in mice which assesses the inhibitoryproperties of a test compound against abdominal constriction responseinduced by the intraperitoneal administration of a noxious agent such asdilute acetic acid or phenylbenzoquinone (hereinafter PBQ) using theprocedure disclosed in European Patent Application No. 0218077.

[0245] Although the pharmacological properties of the compounds of theformula I vary with structural change as expected, in general activitypossessed by compounds of the formula I may be demonstrated at thefollowing concentrations or doses in one or more of the above-mentionedTests (a) and (b):

[0246] Test (a): pA₂>5.3;

[0247] Test (b): ED₃₀ in the range, for example, 0.01-100 mg/kg orally.

[0248] No overt toxicity or other untoward effects were noted in Test(b) when compounds of the formula I are administered at severalmultiples of their minimum inhibitory dose. Prostaglandin receptors andin particular receptors for PGE₂ have been tentatively characterised byKennedy et al. (Advances in Prostaglandin, Thromboxane and LeukotrieneResearch, 1983, 11, 327). The known PGE₂ antagonist SC-19220 blocks theeffect of PGE₂ on some tissues such as guinea pig ileum or dog fundusbut not on other tissues such as the cat trachea or chick ileum. Thosetissues which did possess SC-19220 sensitive mediated effects were saidto possess EP₁ receptors. Based on this compounds of the presentinvention, possessing activity in Test (a), are EP₁ antagonists.

[0249] According to a further feature of the invention there is provideda pharmaceutical composition which comprises a compound of the formula(I) or an in-vivo hydrolysable ester thereof or an amide thereof, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

[0250] The composition may be in a form suitable for oral use, forexample a tablet, capsule, aqueous or oily solution, suspension oremulsion; for topical use, for example a cream, ointment, gel, spray oraqueous or oily solution or suspension; for nasal use, for example asnuff, nasal spray or nasal drops; for vaginal or rectal use, forexample a suppository or rectal spray; for administration by inhalation,for example as a finely divided powder or a liquid aerosol; forsub-lingual or buccal use, for example a tablet or capsule; or orparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

[0251] The amount of active ingredient (that is a compound of theformula (I) or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

[0252] According to a further feature of the invention there is provideda compound of the formula (1) or an in-vivo hydrolysable ester or amideor a pharmaceutically-acceptable salt thereof, for use in a method oftreatment of the animal (including human) body by therapy.

[0253] According to a further feature of the invention there is providedthe use of a compound of the formula I, or an in-vivo hydrolysable esteror amide or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in the relief of pain in the animal(including human) body.

[0254] According to a further feature of the invention there is provideda method for the relief of pain in the animal (including human) body inneed of such treatment which comprises administering to said body aneffective amount of a compound of the formula I, or an in-vivohydrolysable ester or amide or a pharmaceutically-acceptable saltthereof.

[0255] As mentioned above, a compound of the formula (I) is useful intreating the pain which, for example, accompanies inflammatoryconditions such as rheumatoid arthritis and osteoarthritis. In using acompound of the formula I for therapeutic or prophylactic purposes itwill generally be administered so that a daily dose in the range, forexample, 0.1 mg to 75 mg per kg body weight is received, given ifrequired in divided doses. In general lower doses will be administeredwhen a parenteral route is employed. Thus, for example, for intravenousadministration, a dose in the range, for example, 0.05 mg to 30 mg perkg body weight will generally be used. Similarly, for administration byinhalation, a dose in the range, for example, 0.05 mg to 25 mg per kgbody weight will be used.

[0256] Although the compounds of the formula (I) are primarily of valueas therapeutic agents for use in warm-blooded animals (including man),they are also useful whenever it is required to antagonise the effectsof PGE₂ at the EP₁ receptor, based on test a). Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

[0257] By virtue of their ability to relieve pain, the compounds of theformula I are of value in the treatment of certain inflammatory andnon-inflammatory diseases which are currently treated with acyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID)such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen,sulindac, tolmetin and piroxicam. Co-administration of a compound of theformula I with a NSAID can result in a reduction of the quantity of thelatter agent needed to produce a therapeutic effect. Thereby thelikelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the formula (I), or an in-vivohydrolysable ester or amide or pharmaceutically-acceptable salt thereof,in conjunction or admixture with a cyclooxygenase inhibitorynon-steroidal anti-inflammatory agent, and a pharmaceutically-acceptablediluent or carrier.

[0258] The compounds of the invention may also be used with otheranti-inflammatory agents such as an inhibitor of the enzyme5-lipoxygenase (such as those disclosed in European Patent ApplicationsNos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662,0385663, 0385679, 0385680).

[0259] The compounds of the formula (I) may also be used in thetreatment of conditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

[0260] The compounds of the present invention may also be administeredin degradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

[0261] The compositions of the invention may in addition contain one ormore other therapeutic or prophylactic agents known to be of value forthe treatment of pain. Thus for example, a known opiate pain-killer(such as dextropropoxyphene, dehydrocodeine or codeine) or an antagonistof other pain or inflammation mediators, such as bradykinin, takykininand calcitonin gene related peptides (CGRP), or an alpha₂₋adrenoceptoragonist, a GABA_(B) receptor agonist, a calcium channel blocker, asodium channel blocker, a CCK_(B) receptor antagonist, a neurokininantagonist or an antagonist and modulator of the action of glutamate atthe NMDA receptor may usefully also be present in a pharmaceuticalcomposition of the invention.

[0262] The compounds of the present invention may also be administeredin bone diseases such as osteoporosis with calcitonin andbisphosphonates.

[0263] The invention will now be illustrated in the followingnon-limiting Examples in which, unless otherwise stated:

[0264] (i) evaporations were carried out by rotary evaporations in vacuoand work-up procedures were carried out after removal or residual solidsby filtration;

[0265] (ii) yields are given for illustration only and are notnecessarily the maximum attainable;

[0266] (iii) the end-products of the formula I have satisfactorymicroanalysis and their structures were generally confirmed by NMR andmass spectral techniques;

[0267] (iv) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatographic, infra-red (IR) or NMRanalysis;

[0268] (v) melting points are uncorrected and were determined using aMettler SP62 automatic melting point apparatus or an oil-bath apparatus;melting points for the end-products of the formula I were determinedafter recrystallisation from a conventional organic solvent such asethanol, methanol, acetone, ether or hexane, alone or in admixture;

[0269] (vi) the following abbreviations have been used: DMFN,N-dimethylformamide; THF tetrahydrofuran MPLC medium pressure liquidchromatography

EXAMPLE 1

[0270] 4-[N-(2-Benzyloxy-5-bromobenzyl)aminomethyl]Benzoic Acid (Adductwith Acetic Acid)

[0271] To a mixture of ethyl4-[N-(2-benzyloxy-5-bromobenzyl)-aminomethyl]benzoate (1.4 g) inmethanol (25 ml) was added 2N sodium hydroxide solution (7.7 ml). Themixture was heated at reflux for 30 minutes, left to stand for 2 hoursat ambient temperature, the solvent evaporated and the residue mixedwith water (20 ml). The mixture was acidified with acetic acid, theprecipitate filtered off and crystallised form ethyl acetate to give thetitle compound (800 mg) mpt 209° C.

[0272] The starting material was prepared as follows:

[0273] A mixture of 4-aminomethylbenzoic acid (25 g) and concentratedsulphuric acid (25 ml) in ethanol (250 ml) was heated at reflux for 18hours. The volume of solvent was reduced to a third by evaporation. Theresidue poured onto ice (500 g) and basified with concentrated aqueousammonia. The product was extracted with ethyl acetate (3×200 ml) and theextracts dried and evaporated to give ethyl 4-aminomethylbenzoate.

[0274] 2-Benzyloxy-5-bromobenzaldehyde and ethyl 4-aminomethylbenzoatewere heated together at 100° C. for 1 hour. The mixture was cooled,dissolved in ethanol (100 ml) and sodium borohydride (1.3 g) was added.The mixture was stirred for 18 hours at ambient temperature, acidifiedwith acetic acid and water (200 ml) was added. The mixture was extractedwith diethyl ether (4×100 ml), the extracts washed with saturatedaqueous NaHCO₃, dried (MgSO₄), filtered and evaporated to give ethyl4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoate which was purifiedby chromatography on silica gel eluting with CH₂Cl₂ then 5% ethylacetate/CH₂Cl₂ (yield 11.4 g).

EXAMPLE 2

[0275] 4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]Benzoic Acid

[0276] The title compound was prepared from ethyl4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]benzoate using asimilar method to that described in Example 1.

[0277] The starting material was prepared as follows:

[0278] To a suspension of NaH (1.05 g, 50% dispersion in oil) in DMF(100 ml) at 0° C. was added a solution of ethyl4-[N-(2-benzyloxy-5-bomobenzyl)aminomethyl]benzoate dropwise. Themixture was stirred at 0° C. for 1 hour, ethyl iodide (3.43 g) added andthe mixture stirred at ambient temperature for 18 hours. The mixture wasacidified with acetic acid, poured into water (300 ml) and extractedwith ethyl acetate (3×100 ml). The combined extracts were washed withwater (3×100 ml), dried and evaporated. The residue was purified bychromatography eluting with 4% ethyl acetate/CH₂Cl₂ to give ethyl4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]benzoate (yield 6.61g).

EXAMPLE 3

[0279]4-[N-(5-Bromo-2-benzyloxybenzyl)-N-(4-tertbutoxycarbonylphenyl)-Aminomethyl]BenzoicAcid

[0280] tert-Butyl4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate(from example 16) was dissolved in a solution of methanol (10 ml) andtetrahydrofuran (10 ml). To this solution was added aqueous 2N sodiumhydroxide (3 ml) and the solution stirred at ambient temperature for 18hours. The volume of the reaction mixture was reduced by evaporation tohalf the original volume, water (20 ml) was added and the mixtureacidified with acetic acid. The resulting solid was filtered and driedunder vacuum at 60° C. to give the title compound (12 g) m.p. 110° C.

EXAMPLE 4

[0281] 4-[N-(5-Bromo-2-(phenethyl)benzyl)amino]Benzoic Acid

[0282] (A) Methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (0.25g) and 2N aqueous NaOH (5 ml) were heated at reflux in a mixture ofmethanol (5 ml) and THF (5 ml) for 2 hours. The organic solvents wereevaporated, the residue acidified with 2N HCl and extracted with ethylacetate. The extracts were washed with brine, dried (MgSO₄), filteredand evaporated. The residue was purified by crystallisation from diethylether and hexane to give the title compound (0.23 g; mpt 132-134° C.).

[0283] The starting material was prepared as follows:

[0284] (B) A mixture of 5-bromo-2-hydroxybenzoic acid (50 g), methyliodide (31.6 ml) and potassium carbonate (70 g) in DMF (200 ml) wasstirred for 90 hours. The solvent was evaporated, the residuepartitioned between diethyl ether and water, the organic layer waswashed with brine, dried (MgSO₄), filtered and evaporated to give an oil(57.0 g).

[0285] The oil (57.0 g) and 2N NaOH (250 ml) in THF (150 ml) andmethanol (150 ml) was heated at reflux for 1 hour. The solvent wasevaporated, and the residue acidified with 2N HCl solution to give asolid which was isolated by filtration (50.68 g). The solid (50.68 g)was mixed with oxalyl chloride (20 ml), DMF (0.1 ml) and CH₂Cl₂ (300 ml)and stirred for 3 hours. The solvent was evaporated to give a yellowsolid. The solid was dissolved in CH₂Cl₂ (150 ml) and added dropwise toa solution of 2-amino-2-methylpropan-1-ol (42 ml) in CH₂Cl₂ (100 ml) at0° C. The mixture was stirred at ambient temperature for 18 hours,filtered and the filtrate washed sequentially with 2N HCl, water,saturated aqueous NaHCO₃ and brine, dried (MgSO₄), filtered andevaporated. The residue was purified by trituration from diethylether/hexane (1:1) to giveN-(1-hydroxy-2-methylpropan-2-yl)-5-bromo-2-methoxybenzamide (46.34 g).

[0286] (C) Thionyl chloride (36.5 ml) was added dropwise toN-(1-hydroxy-2-methylpropan-2-yl)-5-bromo-2-methoxybenzamide (36.34 g).The resulting solution was stirred for 15 minutes and mixed with diethylether. The diethyl ether was decanted off and the resulting residuedissolved in 20% NaOH solution. The aqueous solution was extracted withdiethyl ether. The extract was washed with brine, dried (MgSO₄) andevaporated to give2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (32.02 g).

[0287] (D) To a solution of methyl2-(N-ethyl-N-(2-phenoxybenzyl)-aminopyridine-5-carboxylate (31.21 g) inTHF (40 ml) was added PhCH₂CH₂MgBr (0.22 mol) as a solution in diethylether (240 ml). The mixture was stirred for 18 hours, the solventsevaporated and the residue partitioned between ethyl acetate andsaturated aqueous ammonium chloride. The organic layer was separated,evaporated and the resulting residue purified by MPLC eluting withdichloromethane to give2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (40.56g).

[0288] (E) To2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (20 g)in diethyl ether (70 ml) at 0° C. was added DIBAL (168 ml, 1 Molsolution in CH₂Cl₂). The mixture was stirred at ambient temperature for18 hours and cooled to 0° C. Aqueous 2N HCl was added to destroy excessDIBAL, the resulting solid was filtered off and suspended in a mixtureof water and ethyl acetate. Triethylamine was added until the whitesolid was dissolved. The organic layer was separated, dried (MgSO₄) andevaporated to give2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (14.21 g).

[0289] (F) A mixture of2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (9.13 g),N-chlorosuccinimide (3.38 g) and dichloromethane (50 ml) was stirred for4 hours. Aluminia (10 g) was added and the mixture stirred for 6 days,filtered and the solvent evaporated. The residue was dissolved indichloromethane (200 ml) and alumina (60 g) added in 6 portions over 8hours. The mixture was filtered, the filtrate evaporated and the residuepurified by MPLC eluting with dichloromethane/hexane (1:1) to give5-bromo-2-(phenethyl)benzaldehyde (3.54 g).

[0290] (G) 5-Bromo-2-(phenethyl)benzaldehyde (1.27 g) and methyl4-aminobenzoate (0.66 g) were heated together at 110° C. for 30 minutesand for a further 30 minutes under vacuum. The mixture was dissolved intoluene, evaporated to dryness, dissolved in ethanol (15 ml). Sodiumborohydride (0.33 g) was added, the mixture stirred for 18 hours, thesolvent evaporated and the residue mixed with acetic acid andpartitioned between saturated aqueous sodium hydrogen carbonate andethyl acetate. The organic layer was washed with brine, dried (MgSO₄),filtered and evaporated. The resulting residue was purified by MPLC,eluting with dichloromethane, to give methyl4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (1.65 g).

EXAMPLE 5

[0291] 4-[N-(2-(Phenethyl)benzyl)-N-ethylamino]Benzoic Acid

[0292] (A) 4-[N-(2-Phenethyl)benzyl)-N-ethylamino]benzoic acid wasprepared from methyl 4-[N-(2-phenethyl)benzyl)-N-ethylamino]benzoateusing a similar method to that of Example 4 paragraph (A) (mpt. 185-186°C.).

[0293] The starting material was prepared as follows:

[0294] (B) A mixture of 2-phenethylbenzoic acid (11.3 g), oxalylchloride (5.2 ml), DMF (0.2 ml) and dichloromethane (100 ml) was stirredfor 1.5 hours. The solvent was evaporated, diglyme (75 ml) added and themixture cooled to −70° C. Lithium tri-(tert-butoxy)aluminium hydride(100 ml, 0.5M solution in diglyme) was added dropwise over 45 minutesmaintaining the reaction temperature below −60° C. The reaction wasstirred at −70° C. for 1 hour and poured into a 2N HCl and ice mixture.The mixture was extracted with iso-hexane (3×100 ml). The extracts werewashed with saturated aqueous sodium hydrogen carbonate, water andbrine, dried (MgSO₄), filtered and evaporated. The residue was purfiedby MPLC eluting with dichloromethane/iso-hexane (1:1) to give2-(phenethyl)benzaldehyde (7.77 g).

[0295] (C) Methyl 4-[N-(2-(phenethyl)benzyl)amino]benzoate was preparedfrom 2-(phenethyl)benzaldehyde and methyl 4-aminobenzoate using asimilar method to that of Example 4 paragraph (G).

[0296] (D) To a mixture of sodium hydride (0.69 g) in DMF (20 ml) wasadded dropwise a solution of methyl4-[N-(2-phenethyl)benzyl)amino]-benzoate (5.41 g) in DMF (30 ml) at 0°C. The mixture was stirred for 30 minutes at 0° C., ethyl iodide (1.4ml) was added and the mixture stirred at ambient temperature for 18hours. The solvent was evaporated, the residue partitioned between ethylacetate and water, the organic layer was washed with brine, dried(MgSO₄), filtered and evaporated.

[0297] The residue was purified by MPLC eluting with dichloromethane togive methyl 4-[N-(2-(phenethyl)benzyl)-N-ethylamino]benzoate (3.07 g).

EXAMPLE 6

[0298] N-Propyl-4-[N-ethyl-N-(2-(phenethyl)benzyl)amino]Benzamide

[0299] 4-[N-(2-(Phenethyl)benzyl)-N-ethylamino]benzoic acid (1.5 g),oxalyl chloride (0.43 ml), DMF (0.1 ml) and CH₂Cl₂ (50 ml) were stirredtogether for 2 hours. The solvent was evaporated and the residuere-dissolved in dichloromethane (100 ml). This was added to a solutionof propylamine (0.35 ml) in dichloromethane (10 ml) at 0° C. Theresulting mixture was stirred for 2 hours at ambient temperature,filtered and the filtrate purified by MPLC, eluting with ethyl acetateto give a gum. The gum was purified by crystallisation from diethylether/iso-hexane to giveN-propyl-4-[N-ethyl-N-(2-(phenethyl)benzyl)-amino]benzamide (0.31 g) asa white solid, (mpt. 91/93° C.).

EXAMPLE 7

[0300] The compounds in the table were prepared from the appropriateacids and amines by a similar method to that described in Example 6.Modifications are described in the footnotes. TABLE 1

Compound Foot- No. R¹ R² X mpt./° C. note 1 H CH₂CH₂OH CH gum 2 H

CH 54-56 a 3 H

CH gum a 4 Br —CH₂CH₂OH CH 126-127 5 Br

CH gum a 6 H —CH₂CH₂OH N gum 7 H —CH₂CH₂OH N gum

EXAMPLE 8

[0301] 4-[N-(5-Bromo-2-(phenethyl)benzyl)-N-ethylamino]Benzoic Acid

[0302] (A) The title compound was prepared from methyl4-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]benzoic acid using asimilar method to that of Example 4 paragraph (A) (mpt 164-165° C.).

[0303] (B) Methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]benzoic acid was prepared from methyl4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate using a similar methodto that described in Example 5 paragraph (D).

EXAMPLE 9

[0304] 2-N-Ethyl-N-(2-(phenethyl)benzyl)amino pyridine-5-carboxylic Acid

[0305] (A) The title compound was prepared from methyl2-[N-ethyl-N-(2-(phenethyl)benzyl)amino]pyridine-5-carboxylate using asimilar method to that of Example 4 paragraph (A) (mpt 113-116° C.).

[0306] The starting material was prepared as follows:

[0307] (B) 6-Chloronicotinic acid (100 g) and concentrated aqueousammonia (500 ml) were heated in a bomb at 170° C. for 6 hours. Themixture was acidified with acetic acid and 2-amino-5-pyridinecarboxylicacid (78.69 g) filtered off.

[0308] (C) A mixture of 2-amino-5-pyridinecarboxylic acid, methanol (900ml) and concentrated sulphuric acid (80 ml) was heated at reflux for 18hours, some of the solvent (500 ml) was evaporated, the pH of theresidue was adjusted to 8 with potassium carbonate and the residue wasextracted with ethyl acetate (3×200 ml). The organic extracts were dried(MgSO₄), filtered and evaporated to give methyl2-amino-5-pyridinecarboxylate (58.18 g).

[0309] (D) Methyl 2-[N-(2-(phenethyl)benzyl)amino]pyridine-5-carboxylatewas prepared from methyl 2-amino-5-pyridinecarboxylate and2-phenethylbenzoic acid by a procedure similar to that described inExample 4 paragraph (G), except that the imine intermediate, methyl2-[N-(2-(phenethyl)benzylidene)amino]-5-pyridinecarboxylate, was formedby heating methyl 2-amino-5-pyridinecarboxylate and 2-phenethylbenzoicacid in a Dean & Starke apparatus in toluene for 18 hours.

[0310] (E) Methyl2-[N-ethyl-N-(2-(phenethyl)benzyl)amino]pyridine-5-carboxylate wasprepared from methyl 2-[N-(2-phenethyl)benzyl)amino]pyridine-5-carboxylate by a procedure similar to described in Example 5paragraph (D).

EXAMPLE 10

[0311]2-[N-(5-Bromo-2-(phenethyl)benzyl)-N-ethylamino]-5-pyridinecarboxylicAcid

[0312] (A) 2-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]-5-pyridinecarboxylic acid was prepared from methyl 2-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate using a similar method tothat described in Example 4 paragraph (A).

[0313] The starting material was prepared as follows:

[0314] (B) Methyl2-[N-(5-bromo-2-(phenethyl)benzyl)-N-ethylamino]-5-pyridinecarboxylatewas prepared from 5-bromo-2-(phenethyl) benzaldehyde and methyl2-amino-5-pyridinecarboxylate using a similar method to that describedin Example 4 paragraph (G) followed by a similar method to thatdescribed in Example 5 paragraph (D).

EXAMPLE 11

[0315] 2-[N-(2-(Benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylic Acid

[0316] Methyl2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate (0.9 g, 2.5mmol) in THF (6 ml) and methanol (6 ml) were treated with 1N aqueoussodium hydroxide (7 ml), and stirred at ambient temperature overnight.The clear solution was evaporated to low bulk, treated with water andglacial acetic acid to pH 4. The resultant white precipitate was stirredfor 15 minutes, filtered, washed well with water, then sucked dry toyield the title product as a white solid (0.8 g, 92%). MS: (M+H)⁺347(M·)⁺346

[0317] The starting material was prepared as follows:

[0318] 2-Benzylbenzyl alcohol (commercial) (1 g) was suspended in 48%aqueous hydrobromic acid (10 ml) and stirred vigorously for 20 hours.The resultant suspended solid was extracted twice with hexane and theextracts dried (MgSO₄) and evaporated to give 2-benzyl benzylbromide asyellow solid (1.3 g, 98%).

[0319] Sodium hydride (0.18 g, 50% in oil, 4.5 mmol) was prewashed withhexane and suspended in sieve-dried DMF (5 ml). To this was added (3.8mmol) methyl 2-ethylaminopyridine-5-carboxylate (0.69 g). The mixturewas stirred at −5° C. for 30 minutes, 2-benzyl benzyl bromide (1 g, 3.8mmol) in DMF (2 ml) added over 3 minutes and the reaction left to stirat ambient temperature overnight. It was then poured into saturatedaqueous ammonium chloride solution (20 ml) and extracted with ethylacetate (×3). The combined extracts were washed with brine, dried andevaporated to give a brown gum (1.7 g). The gum was purified by MPLC onMerck silica (9385) to give methyl2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate as a whitesolid (0.9 g, 66%).

EXAMPLE 12

[0320] 6-(N-Ethyl-N-(2-phenoxybenzyl)amino)pyridazine-3-carboxylic Acid

[0321] 6-(N-Ethyl-N-(2-phenoxybenzylamino)pyridazine-3-carboxamide (0.60g, 1.65 mmol) was dissolved in n-butanol (8.2 ml) and treated withsodium hydroxide (0.186 g, 4.65 mmol). The reaction was heated to refluxfor 2 hours, cooled and evaporated at reduced pressure. The residue wasdiluted with water, acidified with HCl (IN) to pH1 and extracted withethyl acetate (3×). The organic layers were combined, dried (MgSO₄) andevaporated. The residue was purified by chromatography (CH₂Cl₂, MeOH,HOAc) to give the title product as a pale yellow solid (0.5 g, 86%).

[0322] mpt 70-75° C.

[0323] MS(CI⁺): 350 (M+H)⁺

[0324] NMR (200 MHz, DMSO-d₆) δ:1.09 (t, 3H), 3.6 (q, partially obscuredby H₂O), 4.85 (s, 2H), 6.8-7.43 (m, 10H), 7.8 (d, 1H).

[0325] The starting material was prepared as follows:

[0326] Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water(5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02mmol) in THF (25 ml) was added dropwise and the reaction stirred atambient temperature for 2 hours. The volatile components were removed atreduced pressure, aqueous sodium hydroxide (IN, 20 ml) was added and theaqueous solution extracted with dichloromethane (2×). The organic layerswere dried (MgSO₄), evaporated and purified by chromatography (eluant:CH₂Cl₂/EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as ayellow solid (2.2 g, 51%).

[0327] MS (EI⁺): 226 (M+)

[0328] NMR (250 MHz, DMSO-d₆) δ: 1.0 (t,3H), 2.53 (g, partially obscuredby DMSO), 3.7 (5, 2H), 6.88 (m, 3H), 7.05-7.4 (m, 5H), 7.53 (dd, 1H)

[0329] 3-Chloro-pyridazine-6-carboxamide (1.53, 9.69 mmol),N-ethyl-N-(2-(phenoxy)benzyl)amine (2.2 g, 9.69 mmol) anddi-isopropylethylamine (3.87 g, 30 mmol) in DMF (19 ml) was heated to135° C. for 20 hours. The reaction was cooled to ambient temperature andallowed to stand for 48 hours. It was partitioned between ethylacetate/H₂O, the aqueous layer extracted with ethyl acetate and theorganic layers washed with water (4×), dried (MgSO₄) and evaporated. Theresidue was subjected to chromatography (eluant: ethyl acetate/hexane)to give 6-(N-ethyl-N-(2-phenoxybenzylamino)-pyridazine-3-carboxamide asa brown solid (1.53 g, 43%).

[0330] NMR (200 MHz, DMSO-d₆) δ:1.14 (t, 3H), 3.68 (q, 2H), 4.89 (s,2H), 6.85-7.48 (m, 11H), 7.8 (d, 1H), 8.05 (bs, 1H). MS (CI⁺): 349 (MH)⁺

EXAMPLE 13

[0331] 2-(N-ethyl-N-(2-phenoxybenzyl)amino)pyridine-5-carboxylic Acid

[0332] A solution of methyl2-(N-ethyl-N-(2-phenoxybenzyl)amino)pyridine-5-carboxylate (0.65 g, 1.74mmol) in THF (3 ml) and methanol (3 ml) was treated with aqueous sodiumhydroxide (1N, 4 ml). The reaction mixture was heated at reflux for 3hours cooled to ambient and allowed to stand for 60 hours, then heatedat reflux for 3 hours. The organic solvent was evaporated, the residuediluted with water and acidified (pH1) with HCl (conc.). The aqueoussuspension was extracted with ethyl acetate, the organic phase was dried(MgSO₄) and evaporated and the solid was recrystallized from ethylacetate/water and dried under reduced pressure to give the titleproduct.

[0333] mpt 170.5-172.0° C. MS (FAB⁺): 349 (MH)⁺

[0334] NMR (250 MHz, DMSO-d₆) δ: 1.1 (t, 3H), 3.6 (q, 2H), 4.8 (s, 2H),6.6 (d, 1H), 6.9 (d, 1H), 6.98 (m, 2H), 7.13 (m, 3H), 7.26 (m, 1H), 7.38(m, 2H), 7.88 (dd, 1H), 8.6 (d, 1H), 12.3 (bs, 1H).

[0335] The starting material was prepared as follows:

[0336] O-Cresol (4.28 g, 80 mmol), bromobenzene (6,36 g, 40 mmol)potassium carbonate (5.72 g, 41.45 mmol) and copper (I) iodide werecombined in a round bottomed flask under argon. The flask was placed inan ultrasound bath for 30 minutes and then the reaction was heated to140° C. for 16 hours. After cooling to ambient temperature, the reactionmixture was dissolved in dichloromethane and the solution decanted fromthe solid. The organic layer was washed with 1N NaOH (2×), water (2×),dried (MgSO₄) and evaporated to give 2-benzyl phenyl ether which wasused without purification in the subsequent step (5.35 g, 73%).

[0337] NMR (200 MHz, DMSO-d₆) δ: 2.17 (s, 3H), 6.8-7.6 (m, 9H)

[0338] A solution of 2-benzyl phenyl ether (5.35 g, 29.1 mmol) in CCl₄(70 ml) was treated with NBS (5.18 g, 29.1 mmol) and benzoyl peroxide(0.150 g, 0.6 mmol). The reaction was heated to reflux over a highintensity lamp for 3 hours. The reaction wash filtered and the solventevaporated at reduced pressure to give 2-bromomethylphenyl phenyl etherwhich was used without purification in the subsequent step.

[0339] MS CI⁺: 262 [M]⁺

[0340] NMR (200 MHz, DMSO-d₆) δ: 4.7 (s, 2H), 6.8-7.8 (m, 9H)

[0341] A suspension of sodium hydride (1.26 g, 31.5 mmol) in DMF (25 ml)was treated with methyl 2-N-ethyl nicotinate (5.23 g, 29. 1 mmol). Themixture was stirred at ambient temperature for 1 hour and then2-bromomethylphenyl phenyl ether (29.1 mmol) was added. The reaction wasstirred at ambient temperature for 18 hours and then the reactionmixture partitioned between ethyl acetate/water. The organic layer waswashed well with water, dried (MgSO₄) and evaporated. The residue waspurified by chromatography (ethyl acetate/hexane) to give methyl2-(N-ethyl-N-(2-phenoxybenzyl)amino)pyridine-5-carboxylate as a pinksolid (2.2 g, 20%).

[0342] MS FAB⁺: 363 (MH)⁺

[0343] NMR (200 MHz, DMSO-d₆) δ: 1.1 (t, 3H), 3.6 (q, 2H), 3.77 (s, 3H),4.80 (s, 2H), 6.64 (d, 1H), 6.8-7,5 (m, 9H), 7.9 (dd, 1H), 8.62 (d,1H)

EXAMPLE 14

[0344] 6-(N-Ethyl-N-(2-(benzylamino)benzyl)amino)pyridazine-3-carboxylicacid

[0345]6-(N-Ethyl-N-(2-(benzylamino)benzyl)amino)pyridazine-3-carboxamide (0.49g) in n-butanol was treated with sodium hydroxide pellets (140 mg) andheated at gentle reflux for 9 hours. The reaction was allowed to cool,was evaporated to dryness and the residue taken into water and acidifiedwith acetic acid. The mixture was extracted with ethyl acetate (×2) andthe extracts dried and evaporated to give a gum which was purified byMPLC to give the title compound as a brown foam (220 mg, 45%).

[0346] NMR (DMSO-d₆+CD₃ COOD) δ: 1.07-1.20 (t, 3H), 3.55-3.70 (q, 2H),4.35 (s, 2H), 4.90 (s, 2H), 6.45-6.60 (m, 2H), 6.95-7.30 (m, 8H),7.85-7.93 (m,1H).

[0347] MS:363 (M+H)⁺

[0348] The starting material was prepared as follows:

[0349] 2-Nitrobenzylbromide (0.23 mol) in tetrahydrofuran (500 ml) wasadded to a stirred mixture (4.35M) of 70% aqueous ethylamine (350 ml)and water (350 ml) over a 20 minutes. The reaction stood at ambienttemperature for 1 hour, was reduced to low volume, treated withice/water to 800 ml and basified with an aqueous solution of sodiumhydroxide (ION, 23 ml). It was extracted with ether (2×) and thecombined extracts dried (MgSO₄) and evaporated to giveN-ethyl-2-nitrobenzylamine as a yellow oil (44 g, 100%).

[0350] NMR (CDCl₃) δ: 1.03-1.13 (t, 3H), 2.57-2.63 (q, 2H), 3.98 (s,2H), 7.30-7.37 (m, 1H) 7.45-7.6 (m, 2H), 7.85-7.9 (dd, 1H).

[0351] N-Ethyl-N-(2-nitrobenzyl)amine (4 g, 22 mmol) in ethanol (100 ml)was treated with 10% palladium-on-carbon (180 mg) and hydrogenated atN.T.P. for 2 hours. When uptake of hydrogen had ceased the reaction wasfiltered through Celite and evaporated to giveN-ethyl-N-(2-aminobenzyl)amine (3.3 g, 100%).

[0352] NMR (CDCl₃) δ: 1.08-1.15 (t, 3H), 2.63-2.74 (q, 2H), 3.60 (br,1H), 3.80 (s, 2H) 6.63-6.70 (m, 2H), 7.01-7.12 (m, 2H).

[0353] N-Ethyl-N-(2-aminobenzyl)amine (707 mg, 4.7 mmol) in DMF (11 ml)was treated with 6-chloropyridazin-3-amide (4.7 mmol) followed bydiisopropylethylamine (15.4 mol) and the reaction stirred at 140° underargon for 24 hours. The reaction was evaporated in vacuo (cold-finger)and the residue partitioned between water and ethyl acetate. Thecombined organic extracts were dried and evaporated to give a brown gum.The gum was purified by medium pressure chromatography to give6-(N-ethyl-N-(2-aminobenzyl)amino)-pyridazine-3-carboxamide (500 mg,30%).

[0354] NMR (DMSO-d₆) δ: 1.08-1.15 (t, 3H), 3.55-3.70 (q, 2H), 4.69 (s,2H), 5.0-5.3 (br, 2H), 6.49-7.03 (m, 5H), 7.79-7.84 (d, 1H), 7.45 (br,1H), 8.09 (br, 1H).

[0355] 6-(N-Ethyl-N-(2-aminobenzyl)amino)pyridazine-3-carboxamide (2.06mmol) was part dissolved in methanol (12 ml) and treated withbenzaldehyde (240 mg, 2.25 mmol) followed by NaBH₃CN (130 mg, 2.06mmol). The reaction was stirred at ambient temperature for 9 days. Itwas then acidified to pH 2, stirred for 10 minutes to destroy excessNaBH₃CN, basified with sodium hydroxide and extracted with ethyl acetate(×2). The combined extracts were dried and evaporated to give a palebrown gum (1.3 g) which was purified by MPLC to give6-(N-ethyl-N-(2-(benzylamino)benzyl)amino)pyridazine-3-carboxamide as awhite solid (0.49 g, 66%).

[0356] NMR (DMSO-d₆)δ: 1.05-1.20 (t, 3H), 3.55-3.70 (q, 2H), 4.33 (s,2H), 4.80 (s, 2H), 6.05-6.25 (br, 1H), 6.47-6.50 (d, 1H), 6.87-7.32 (m,9H), 7.80-7.85 (d, 1H), 7.42 (br, 1H), 7.98 (br, 1H).

[0357] MS: 362 (M+H)⁺

EXAMPLE 15

[0358]6-[N-(5-Bromo-2-benzylaminobenzyl)-N-ethylaminolpyridazine-3-carboxylicAcid

[0359] A mixture of6-[N-(5-bromo-2-benzylaminobenzyl)-N-ethylamino]pyridazine-3-carboxylate(700 mg, 1.59 mmol), sodium hydroxide pellets (200 mg, 5.0 mmol) andbutanol was stirred at reflux for 3 hours. The mixture was cooled,diluted with water (100 ml) and washed with hexane (2×100 ml). Theaqueous layer was acidified with formic acid and extracted withdichloromethane (2×200 ml). The combined organic extracts were driedover anhydrous magnesium sulphate and evaporated to give a white solid,which was triturated with ether and filtered to give the title compound(500 mg).

[0360] m.p. 176° C.-dec.

[0361] NMR (200 MHz, DMSO-d₆) δ: 1.13 (t, J=7 Hz, 3H); 3.64 (q, J=7 Hz,2H); 4.33 (d, J=5 Hz, 2H); 4.83 (s, 2H); 6.15 (broad t, J=5 Hz, 1H);6.45 (d, J=8 Hz, 1H); 6.98-7.30 (m, 8H); 7.85 (d, J=8 Hz, 1H).

[0362] MS (ESP⁺): 441/443 (M+H)⁺(1×Br)

[0363] The starting material was prepared as follows:

[0364] Stannous chloride dihydrate (22.5 g, 0.1M) was added in oneportion to a stirred mixture of N-ethyl-5-bromo-2-nitrobenzylamine (8.5g, 32.8 mmol) and 36% hydrochloric acid (20 ml, 0.22M) in ethanol (250ml) at ambient temperature. There was an exothermic reaction (50° C.)and a yellow solution formed, which was stirred for 1 hour allowing itto cool. The solvent was evaporated at reduced pressure and the residuedissolved in ethanol (100 ml) and stirred while diluting with ether (200ml) until crystallisation occurred. The yellow solid was filtered offand washed with ether to give N-ethyl-5-bromo-2-aminobenzylamine as asalt, from which the free base was isolated by stirring with 2N sodiumhydroxide solution (150 ml) and extracting into ether. The organic layerwas dried over anhydrous magnesium sulphate and evaporated to give anoil (4.2 g).

[0365] NMR (200 MHz, CDCl₃) δ: 1.10 (t, J=7 Hz, 3H); 2.64 (q, J=7 Hz,2H); 3.75 (s, 2H); 6.50 (dd, J=8, 2 Hz, 1H); 7.1-7.2 (m, 2H).

[0366] MS (CI⁺): 228/230 M+(1×Br)

[0367] A mixture of N-ethyl-5-bromo-2-aminobenzylamine (4.2 g, 18.3mmol), 6-chloropyridazine-3-carboxamide (3.0 g, 19.0 mmol), ethyldi-isopropylamine (7.0 ml) and DMF (50 ml) was stirred at 140° C. underargon for 16 hours. The mixture was cooled, evaporated at reducedpressure, the residue was then partitioned between 1N sodium hydroxidesolution (100 ml) and a mixture of ethyl acetate, dichloromethane andmethanol (10:10:1, 500 ml). The organic layer was separated, dried overanhydrous magnesium sulphate and evaporated to give a yellow solid (6.0g). Crystallisation from ethyl acetate (500 ml) gave6-[N-(5-bromo-2-aminobenzyl)-N-ethylamino]pyridazine-3-carboxamide asyellow rosettes (118 g) m.p. 208-210° C.

[0368] NMR (200 MHz, DMSO-d₆) δ: 1.13 (t, J=7Jz, 3H); 3.62 (q, J=7 Hz,2H); 4.68 (s, 2H); 5.33 (s, 2H); 6.63 (d, J=8 Hz, 1H); 6.9-7.15 (m, 3H);7.45 (broad s, 1H); 7.85 (d, J=8 Hz, 1H); 8.10 (broad s, 1H).

[0369] MS (CI⁺): 349/351 (M+H)⁺(1×Br)

[0370] Analysis: Calc % C, 48.0; H, 4.6; N, 20.0

[0371] Found % C 48.0, H4.6, N19.7

[0372] To a mixture of6-[N-(5-bromo-2-aminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (900mg, 2.57 mmol), benzaldehyde (0.6 ml, 5.9 mmol) and methanol (50 ml)stirred at 50° C., was added portionwise sodium cyanoborohydride (400mg, 6.36 mmol). The solution was stirred for 16 hours at 20° C., bywhich time the product crystallised. It was filtered off and washed withmethanol (10 ml) to give6-[N-(5-bromo-2-benzylamino)-N-ethylamino]pyridazine-3-carboxamide (850mg) m.p. 160-162° C.

[0373] NMR (200 MHz, DMSO-d₆) δ: 1.12 (t, J=7 Hz, 3H); 3.60 (q, J=7 Hz,2H); 4.33 (s, 2H); 4.80 (s, 2H); 6.43 (d, J=8 Hz, 1H); 7.00-7.25 (m,8H); 7.45 (broad s, 1H); 7.35 (d, J=8 Hz, 1H); 8.0 (broad s, 1H).

[0374] MS (ESP+): 440/442 (M+H)⁺(1×Br)

EXAMPLE 16

[0375]4-1N-(5-Bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoicAcid

[0376] tert-Butyl4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate(1.79 g) was suspended in formic acid (10 ml) and heated on a steam bathuntil a clear solution formed. The reaction mixture was cooled and stoodat ambient temperature for 18 hours. The resulting solid was filteredand washed with formic acid (2×5 ml) and dried under vacuum at 60° C. togive the title product (1.4 g).

[0377] The starting material was prepared as follows:

[0378] 5-Bromo-2-benzyloxybenzoic acid [International patentapplication, publication no. WO 96/03380] and tert-butyl-4-aminobenzoatewere heated on a steam bath for 2 hours. Ethanol (50 ml) andtetrahydrofuran (50 ml) were added to the hot reaction mixture. Thesolution was allowed to cool and sodium borohydride (1.4 g) was added.The reaction mixture was then stirred at ambient temperature for 3hours, poured into water (200 ml) and extracted with dichloromethane(4×100 ml). The combined extracts were dried over magnesium sulphatetert-butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate which was usedwithout further purification (18 g).

[0379] tert-Butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate (16.9 g)and methyl-4-bromomethylbenzoate were dissolved in in dimethylformamide(30 ml) and potassium carbonate (18 g) added. The mixture was stirred atambient temperature for 24 hours and then poured into water (300 ml).The reaction mixture was extracted with ether (4×100 ml). The combinedether extracts were washed with water (3×100 ml) and brine (1×100 ml),dried over magnesium sulphate and evaporated. The residue was purifiedby MPLC eluting with 1:1 dichloromethane/hexane to give tert-butyl4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate(3.6 g) m.p. 154-155° C.

EXAMPLE 17

[0380]4-[N-(5-Bromo-2-benzyloxybenzyl)-N-(4-carboxybenzyl)aniinolbenzoic Acid

[0381] tert-Butyl4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-carboxybenzyl)-amino]benzoate(example 3) (500 mg) was suspended in formic acid (2 ml) and heated on asteam bath until a clear solution was obtained. This solution was leftat ambient temperature for 18 hours and the resulting solid filtered,washed with formic acid (2×1 ml) and dried under vacuum at 60° C. togive the title product (340 mg) m.p. 271° C.

EXAMPLE 18

[0382] 4-[2-Benzyloxybenzylthio]benzoic Acid

[0383] Sodium hydride (6.5 g, 50% dispersion in oil) in DMF (100 ml) wascooled (0° C., ice bath) and 4-thiobenzoic acid (10 g) was added. Afterstirring for 30 minutes at 0° C., 2-bromomethylphenyl benzyl ether (18.6g) as a solution in DMF (100 ml) was added. The reaction was stirred atambient temperature for 18 hours, cooled (ice bath), water was added,and the mixture acidified with acetic acid. The resulting solid wasisolated by filtration and recrystallised from methanol to give4-[2-benzyloxybenzylthio]benzoic acid (24 g) (mpt. 144° C.).

EXAMPLE 19

[0384] N-(3-Pyridyl)-4-[2-benzyloxybenzylthio]benzamide

[0385] To a stirred mixture of 3-aminomethylpyridine (324 mg) andtriethylamine (1.51 g) in dichloromethane (20 ml) at 0° C. was added4-[2-benzyloxybenzylthio]benzoylchloride in CH₂Cl₂ (10 ml) (3 mmol). Themixture was allowed to warm to ambient temperature, washed withsaturated aqueous NaHCO₃ (3×20 ml), dried (MgSO₄), filtered andevaporated. The residue was triturated with diethyl ether (20 ml) andcrystallised from ethyl acetae to giveN-(3-pyridyl)-4-[2-benzyloxybenzylthio]benzamide (220 mg). (mpt. 108°C.).

[0386] The starting material was prepared as follows:

[0387] 4-[2-benzyloxybenzylthio]benzoic acid (6.3 g) and oxalyl chloride(2.26 g) were stirred in dichloromethane (100 ml) for 18 hours. Thesolvent was evaporated to give 4-[2-benzyloxybenzylthio]benzoylchloridewhich was dissolved in dichloromethane.

EXAMPLE 20

[0388] The compounds in the following table were prepared from4-[2-benzyloxybenzylthio]benzoylchloride and the appropriate amine usinga similar method to that described in Example 19. TABLE

Compound No. R mpt./° C. Footnote 1 CH₂CH₂OH 112 2 —CH₂CH₂CH₃  98 a 3

156-158

EXAMPLE 21

[0389] 4-(2-(Benzyloxy)benzyloxy)benzoic Acid

[0390] Methyl 4-(2-(benzyloxy)benzyloxy)benzoate (1.01 g, 1.91 mmol) wasdissolved in THF (20 ml) and methanol (7 ml). The solution was treatedwith NaOH (IN, 6 ml). The reaction was heated at reflux for 3 hours andthen concentrated at reduced pressure. The pH was adjusted to pH1 withconcentrated HCl and the solid filtered, washed with water and dried togive the title compound as a white solid (0.9 g, 98%).

[0391] mpt 176.8-178.8° C.

[0392] Elemental Analysis for C₂₁H₁₈O₄.0.2H₂O calc 74.6% C 5.40% H found74.8% C 5.40% H

[0393] NMR (200 MHz, DMSO-d₆) δ: 5.2 (s, 4H), 7.05 (m, 4H), 7.4 (m, 7H)7.68 (d, 2H).

[0394] The starting material was prepared as follows:

[0395] A solution of methyl 4-hydroxybenzoate in DMF (5 ml) was treatedwith K₂CO₃ (2.76, 20 mmol) and 2-benzyloxy benzyl bromide (1.52 g, 10mmol). The reaction was stirred at ambient temperature over night. Thereaction mixture was partitioned between ethyl acetate and water and theorganic phase was washed well with water dried (MgSO₄) and evaporated.The crude material was purified by chromatography [EtOAc:hexane] to givemethyl 4-(2-(benzyloxy)benzyloxy)benzoate as a white solid (3.06 g,88%).

[0396] MS (FAB⁺): 349 [M+H]⁺

[0397] NMR (200 MHz, DMSO-d₆) δ: 3.81 (s, 3H), 5.2 (bs, 4H), 6.97 (m,1H) 7.12 (m, 3H), 7.37 (m, 7H), 7.9 (m, 2H).

EXAMPLE 22

[0398] 4-(1-(2-(Benzyloxy)phenyl)ethoxy)benzoic Acid

[0399] Methyl 4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate (0.5 g, 1.4mmol) was dissolved in THF (5 ml) and methanol (5 ml). The solution wastreated with sodium hydroxide (IN, 6 ml) and the reaction heated at 60°for 3 hours. The solvent was removed at reduced pressure and thereaction mixture diluted with water and extracted with ethyl acetate.The aqueous phase was acidified (pH1) with concentrated HCl andextracted with ethyl acetate (3×). The organic phases were combined,dried (MgSO₄) and evaporated to give the title compound as a white solid(0.33 g, 68%). mpt: 203-204° C.

[0400] Elemental Analysis for C₂₂H₂₀ 04.0.3H₂O

[0401] calculated: C%:7.47H%:5.9

[0402] found: C%:74.5H%:5.8

[0403] MS (FAB⁻): 347 (M−H)—

[0404] NMR (200 MHz, DMSO-d₆) δ: 1.56 (d,3H) 5.24 (s,2H) 5.80 (q, 1H),6.9(m, 3H), 7.3 (m, 8H), 7.77 (d, 2H), 12.46 (bs, 1H).

[0405] The starting material was prepared as follows:

[0406] A solution of 2-benzyloxybenzaldehyde (4.24 g, 20 mmol) in THF(20 ml) was cooled to 0° C. and treated with a solution of methyllithium (1.4 M in diethyl ether 21.4 ml, 30 mmol). The reaction wasstirred for 30 minutes at 0° C., then quenched with water andpartitioned between ethyl acetate and water. The aqueous phase wasextracted with ethyl acetate (2×) and the organic phases were combined,dried (MgSO₄) and evaporated to give 1-(2-benzyloxy)ethanol as acolourless oil (4.62 g, quantitative) which was used withoutpurification in the subsequent step.

[0407] NMR (250 MHz, DMSO-d₆) δ:1.3 (d, 3H), 4.93 (d, 1H) 5.08 (m, 3H),6.96 (m, 2H), 7.17 (m, 1H) 7.4 (m, 6H)

[0408] A solution of 1-(2-benzyloxy)ethanol (4.56 g, 20 mmol) in THF (80ml) was treated with methyl 4-hydroxybenzoate (3.34 g; 22 mmol),triphenylphosphine (5.76 g, 22 mmol) and diethyl azodicarboxylate (4.03g, 22 mmol). The reaction was stirred at ambient temperature for 3½hours. The solvent was evaporated at reduced pressure and the residuetriturated with hexane and then filtered. The filtrate was evaporated,purified by chromatography (eluant:diethyl ether/hexane) to give methyl4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate as a white solid (2.99 g, 41%)mp 90.8-91.5° C.

[0409] MS (CI⁺): 363 [M H⁺]

[0410] Elemental Analysis for C₂₃H₂₂O₄

[0411] calc C%: 76.2%: H%: 6.12%

[0412] found C%: 76.1: H%: 6.0

[0413] NMR (250 MHz, DMSO-d₆) δ: 1.57 (d, 3H), 3.78 (s, 3H), 5.25 (s,2H), 5.82 (q, 1H), 6.9 (m, 3H), 7.35 (m, 8H), 7.8 (d, 2H).

[0414] The mixture was allowed to warm to ambient temperature, washedwith saturated aqueous NaHCO₃ (3×20 ml), dried (MgSO₄), filtered andevaporated. The residue was triturated with diethyl ether (20 ml) andcrystallised from ethyl acetate to give4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoic acid (220 mg). (mpt. 108° C.).

[0415] Methyl 4-(2-(benzyloxy)benzyloxy)benzoate (6.3 g) and oxalylchloride (2.26 g) were stirred in dichloromethane (100 ml) for 18 hours.The solvent was evaporated to give 1-(2-benzyloxy)ethanol which wasdissolved in dichloromethane.

EXAMPLE 23

[0416] 4-(2-(phenethyl)benzyloxy)benzoic Acid

[0417] The title compound was prepared from methyl4-(2-(phenethyl)benzyloxy)benzoate using a similar method to that ofexample 21. m.p. 178-180° C.

[0418] MS (FAB⁻): 331 (M—H)

[0419] Elemental Analysis C₂₂H₂₀O₂₀O₃

[0420] Calculated % C79.5, H6.06

[0421] Found % C79.4, H6.0

[0422] NMR (200 MHz, DMSO-d₆) δ:2.9 (m, 4H); 5.14 (s, 2H); 7.18 (m,10H); 7.42 (d, 1H); 7.89 (m, 2H); 12.6 (bs, 1H).

[0423] The starting material was prepared as follows:

[0424] A solution of 2-(phenethyl)benzyl alcohol (0.424 g, 2 mmol) intoluene (25 ml) was treated with methyl 4-hydroxybenzoate (0.334 g, 2.2mmol), triphenylphosphine (0.786 g, 3 mmol) and diethylazodicarboxylate(0.522 g, 0.47 ml, 3 mmol). The reaction was stirred at ambienttemperature overnight and then diluted with ethyl acetate and washedwith water and brine. The organic layer was dried over MgSO₄ andevaporated. The residue was purified by chromatography (eluant:ether/hexane) to give the methyl ester as a white solid (0.58 g, 84%).

[0425] NMR (200 MHz, DMSO-d₆) δ:2.90 (m, 4H); 3.82 (s, 3H); 5.16 (s,2H); 7.2 (m, 10H); 7.43 (bd, 1H); 7.93 (m, 2H).

EXAMPLE 24

[0426] 4-[3-(2-Phenethylphenyl)propyl]benzoic Acid

[0427] (A) To a solution of methyl4-[3-(2-phenethyl)phenyl)propyl]benzoic acid (6.25 g) in a mixture ofTHF (50 ml) and methanol (50 ml), was added 2N sodium hydroxide (42.5ml). The mixture was stirred for 18 hours, the solvent volume reduced byhalf by evaporation and the residue poured into water and washed withdiethyl ether. The aqueous layer was acidified with acetic acid andextracted with ethyl acetate (3×100 ml). The extracts were dried(MgSO₄), filtered and evaporated to give the title compound (5.24 g);mpt 97-98° C.

[0428] The starting material was prepared as follows:

[0429] A mixture of 2-(phenethyl)benzoic acid (commercially available)(11.3 g), oxalyl chloride (5.2 ml), and DMF (2 drops) in dichloromethane(100 ml) was stirred for 1.5 hours. The resulting solution wasevaporated and the residue dissolved in diglyme (75 ml) and cooled to−70° C. Li(O^(t)Bu)₃H (100 ml of 0.5M solution in diglyme) was addeddropwise over 45 minutes and the mixture stirred at −70° C. for 1 hour.The solution was poured into 2N aqueous hydrochloric acid and themixture extracted with iso-hexane (3×100 ml). The combined extracts werewashed with saturated aqueous sodium hydrogen carbonate, water and brineand dried (MgSO₄). The solvent was evaporated and the residue purifiedby medium pressure chromatography on silica gel eluting with a mixtureof dichloromethane and iso-hexane (1:1) to give 2-(phenethyl)benzoicacid as a colourless oil (7.77 g).

[0430] Lithium bis(trimethylsilyl)amide (56.7 ml, 1.0M solution in THF)was added to a mixture of 4-carboxyphenethyltriphenylphosphonium bromide(13.44 g, prepared from 4-(2-bromoethyl)benzoic acid by a standardmethod) in THF (100 ml), under argon and stirred for 1 hour.2-Phenethylbenzaldehyde (5.75 g) in THF (50 ml) was added and themixture stirred for 18 hours. The solvent was evaporated and the residuepartitioned between water and diethyl ether. The aqueous layer wasacidified with 2N HCl, and extracted with ethyl acetate (3×150 ml). Theorganic extracts were washed with brine, dried (MgSO₄), filtered andevaporated to give an oil (9.38 g). The oil (9.38 g) was dissolved inmethanol (150 ml) and concentrated sulphuric acid heated at 100° C. for12 hours, evaporated, mixed with water and extracted with diethyl ether(3×150 ml). The organic extracts were washed with saturated sodiumhydrogen carbonate and water, dried (MgSO₄), filtered and evaporated.The residue was purified by MPLC eluting with dichloromethane: petroleumether (1:1) to give an oil (6.96 g). The oil was dissolved in ethylacetate (200 g) and added to 10% palladium on carbon (0.7 g). Theresulting mixture was stirred under hydrogen for 18 hours, filteredthrough Celite and evaporated to give methyl4-[3-(2-phenethyl)phenyl)propyl]benzoic acid as an oil (6.25 g).

EXAMPLE 25

[0431] N-(2-Hydroxyethyl)-4-[3-(2-(phenethyl)phenyl)propyl]benzamide

[0432] (A) A mixture of 4-[3-(2-phenethylphenyl)propyl]benzoic acid (2.0g), oxalyl chloride (0.56 ml) and DMF (0.1 ml) in dichloromethane (50ml) was stirred for 4 hours. The solvent was evaporated to give an oil(2,2 g). To a stirred solution of ethanolamine (0.55 ml) indichloromethane (50 ml) at 0° C. was added the oil (1.1 g) indichloromethane (10 ml). The reaction was warmed to ambient temperatureand stirred for 18 hours. The mixture was washed with water, dried(MgSO₄), filtered and evaporated to give a white solid. The solid waspurified by crystallisation from ethyl acetate to give the titlecompound (811 mg); mpt 104-106° C.

EXAMPLE 26

[0433] 4-[2(Phenethyl)phenethyl]benzoic Acid

[0434] The title compound was prepared from methyl4-[2-(phenethyl)phenethyl]benzoic using a similar method to that ofExample 24 paragraph (A).

[0435] The starting material was prepared as follows:

[0436] Methyl 4-[2-(phenethyl)phenethyl]benzoic acid was prepared fromhenethylbenzaldehyde and 4-carboxybenzyltriphenylphosphonium bromideusing a similar method to the described in Example 24 for thepreparation of methyl 4-[3-(2-(phenethyl)phenyl)propyl]benzoic acid.

EXAMPLE 27

[0437] The compounds in the table were prepared from the acids4-3-(2-phenethylphenyl)propyl]benzoic acid or4-[2-(phenethyl)phenethyl]benzoic acid and the appropriate amines by asimilar method to that described in Example 25 with the modificationsdescribed in the footnotes.

Compound No. n R mpt./° C. Footnote 1 3

59-61 a, b 2 3 CH₂CH₂CH₃ 61-63 c 3 2 CH₂CH₂OH 72-75 d

EXAMPLE 28

[0438] 4-[3-(2(Benzylamino)phenyl)propyl]benzoic Acid

[0439] (A) To a solution of ethyl4-[3-(2-(benzylamino)phenyl)propyl]benzoate (1 g) in methanol (50 ml)was added 1N sodium hydroxide (13.4 ml). The mixture was stirred for 2hours, heated at reflux for 10 minutes, the solvent was evaporated, theresidue mixed with water (50 ml) and acidified to pH 4 with 2N HCl. Themixture was extracted with ethyl acetate (3×20 ml) and the extractswashed with brine (2×20 ml), dried (MgSO₄), filtered and evaporated. Theresidue was triturated with petroleum ether (60-80) (25 ml) to give thetitle compound (0.55 g; 1180C).

[0440] The starting material was prepared as follows:

[0441] (B) Ethyl 4-[3-(2-(benzylamino)phenyl)propyl]benzoate wasprepared as follows: To a stirred suspension of LiOH H₂O (3.8 g) inethanol (100 ml) was added a solution of 2-nitroacetophenone (15 g) andmethyl 4-formylbenzoate (14.9 g) in ethanol (50 ml). The mixture wasstirred for 20 minutes and the resulting solid filtered off and dried(22 g). A portion of this material (6.0 g) was dissolved intrifluoroacetic acid (100 ml), mixed with 10% palladium/carbon (1.0 g)and stirred vigorously under hydrogen for 24 hours. The solution wasfiltered through Celite, the solvent evaporated and the residue mixedwith water. The mixture was neutralised with sodium hydrogen carbonate,and extracted with diethyl ether (3×50 ml). The extracts were dried(MgSO₄), filtered and evaporated. The residue was purified by flashchromatography with dichloromethane and ethyl4-[3-(2-aminophenyl)propyl]benzoate (3.21 g) and eluted with 10% ethylacetate/dichloromethane. A mixture of ethyl4-[3-(2-aminophenyl)propyl]benzoate (3.21 g) and benzaldehyde (1.21 g)was heated at 100° C. for 1 hour.

[0442] The mixture was dissolved in diethyl ether (25 ml), dried(MgSO₄), filtered and evaporated. The residue was dissolved in ethanol(100 ml) and sodium cyanoborohydride (0.5 g) was added. The mixture wasstirred for 20 minutes, sodium cyanoborohydride (0.5 g) was added, themixture was stirred for a further 1 hour, sodium cyanoborohydride (0.5g) was added and the mixture was stirred for 18 hours. The mixture waspoured into water (100 ml), acidified with acetic acid and extractedwith diethyl ether (3×50 ml). The extracts were dried (MgSO₄), filteredand evaported. The residue was purified by flash chromatography elutingwith 60% dichloromethane/petroleum ether to give ethyl4-[3-(2-(benzylamino)phenyl)propyl]benzoate (3.8 g).

EXAMPLE 29

[0443] The compounds in the table were prepared from the correspondingethyl esters by a similar method to that of Example 28 paragraph (A)with the modifications described in the footnotes.

[0444] The ester precursors were prepared as described in the footnotes.

Compound No. R mpt./° C. Footnote 1 CH₂Ph 133 a, b 2 Me a, c

EXAMPLE 30

[0445] 4-[2-(2-(Phenethyl)-3-pyridyl)ethyl]benzoic

[0446] Methyl 4-[2-(2-(phenethyl)-3-pyridyl)ethyl]benzoate (0.46 g, 1.3mmol) was dissolved in ethanol (10 ml) and treated with NaOH (IN, 2.66ml). The reaction was stirred at ambient temperature for 60 hours. Thereaction mixture was partially evaporated and neutralized with HCl. Theprecipitate was filtered, taken up in hot ethanol and filtered. Thefiltrate was evaporated, the residue was taken up in aqueous sodiumhydroxide and acetic acid added which gave a precipitate.

[0447] The title product was recrystallised from ethanol/water (0.118mg).

[0448] m.p. 152.1-153.0° C.

[0449] MS (CI⁺): 332 [M+H]⁺

[0450] The starting material was prepared as follows:

[0451] A solution of sieve dried di-isopropylamine (3.24 g, 32 mM) inTHF (20 ml) was cooled to −50° C. under argon and treated with n-butyllithium (1.6 M in hexane, 19.2 ml). A suspension of 2-methyl nicotinicacid (2.0 g, 14.6 mmol) in THF (70 ml) was added slowly by syringe tothe reaction mixture. A deep red/purple colour developed. The reactionwas stirred for 0.75 hours allowing the temperature to rise to −40° C.The reaction was cooled to −60° C. A solution of benzaldehyde (1.86 g,17.52 mmol) in THF (10 ml) was added dropwise keeping the temperaturebelow −60° C. The colour of the reaction discharged to pale yellowwithin 15 minutes. The cooling bath was removed and the reaction wasallowed to warm to 0° C. and was held at 0° C. for 18 hours. Water wasadded and the reaction acidified to pH 2 with 1N HCl and extracted withEtOAc. The pH of the aqueous phase was adjusted to pH 5 and re-extractedwith EtOAc. The organic layers were combined, dried (56 mg) andevaporated. The resulting pale yellow oil was purified by chromatographyeluting with (methanol/dichloromethane) to give2-phenyl-8-oxopyrano[4,3-b]pyridine as a yellow oil (1.5 g)

[0452] MS (CI⁺): 226 [M+H]⁺.

[0453] To a cooled solution (−70° C.) of2-phenyl-8-oxopyrano[4,3-b]pyridine (1.09 g, 4.84 mmol) indichloromethane (25 ml) was added DIBAL (IM in dichloromethane, 9 ml)keeping the temperature below −65° C. The reaction mixture was held at−70° C. for 4 hours. The reaction mixture was quenched by addingMeOH/dichloromethane (5 ml) (1/1), allowed to warm to ambienttemperature and poured onto a slurry of SiO₂ and dichloromethane. Thesilica slurry was applied to the top of a chromatography column whichwas eluted with methanol/dichloromethane to give2-phenyl-8-hydroxypyrano-[4,3-b]pyridine as a pale yellow solid (0.89 g,81%). (It was used immediately in the following step)

[0454] MS (FAB⁺) 228 [M+H]⁺.

[0455] 4-Methoxycarbonylbenzyltriphenylphosphonium bromide (3.87 g 7.88mmol) was suspended in THF (10 ml) and flushed with argon. Lithiumbis(trimethylsilyl)amide (IM in THF, 8.66 ml) was added and the reactionstirred at ambient temperature for 0.75 hours (a deep orange colourdeveloped). A suspension of 2-phenyl-8-hydroxypyrano-[4,3-b]pyridine(0.89 g, 3.94 mmol) in THF (10 ml) was added slowly. The reaction wasstirred at ambient temperature overnight, then quenched by adding water,neutralised with hydrochloric acid, extracted with ethyl acetate, dried(MgSO₄) and evaporated. The crude material was purified bychromatography (eluting with EtOAc/hexane) to give methyl4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethenyl]benzoate as thecis and trans isomers (0.95 g, 67%)

[0456] MS (CI⁺): 360 [M+H]⁺.

[0457] Methyl4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethenyl]benzoate (0.463 g,1.29 mmol) was dissolved in ethanol (15 ml), acetic acid (3 drops) and10% palladium on carbon (0.05 g).

[0458] The reaction was placed under a hydrogen atmosphere and stirredfor 18 hours. The reaction was then filtered and evaporated to givemethyl 4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate asan oil (0.47 g)

[0459] MS(CI⁺): 362 [M+H]⁺.

[0460] Methyl4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.47 g),1.29 mmol) was cooled in an ice bath. Thionyl chloride (15 ml) was addedand the reaction held at 0° C. for 1 hour. The reaction mixture wasevaporated and azeotroped with toluene to give methyl4-[2-(2-(2-chloro-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.549 g)which was used without further purification.

[0461] MS (CI⁺): 380 [M+H]⁺.

[0462] Methyl4-[2-(2-(2-chloro-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.537 g,1.29 mmol) was dissolved in ethanol (10 ml). The solution was treatedwith palladium on carbon (10% Pd, 0.1 g) and placed under a hydrogenatmosphere. The reaction was stirred at ambient temperature for 18hours, then filtered and the solvent evaporated to give methyl4-[2-(2-(phenethyl)-3-pyridyl)ethyl]benzoate (0.467 g), which was usedwithout further purification.

[0463] MS (CI⁺): 346 [M+H]⁺

EXAMPLE 31

[0464] 4-[2-(4-(Phenethyl)pyrid-3-yl)ethyl]benzoic Acid

[0465] tert-Butyl 4-[2-(4-(phenethyl)pyrid-3-yl)ethyl]benzoate (0.36 g,0.95 mmol) was dissolved in dichloromethane (5 ml) and treated withtrifluoroacetic acid (0.5 ml). The reaction was stirred at ambienttemperature for 5 hours, then partitioned between ethyl acetate andbuffer (pH 6). The layers were separated and the aqueous layer extractedwith ethyl acetate. The organic layers were combined, dried (MgSO₄) andevaporated to give the title product (0.168 g) as a salt with THF.

[0466] MS [CI⁺]: 332 [M+H]⁺

[0467] Elemental Analysis for C₂₂H₂₁NO₂.CF₃CO₂H:

[0468] Calc: 63.5%C, 5.08%H, 3.1%N

[0469] Found: 63.5%C, 4.7%H, 2.8%N

[0470] The starting material was prepared as follows:

[0471] A solution of di-isopropylamine (3.44 g, 34.1 mmol) was cooled to−78° C. and treated with n-butyl lithium 1.6 M, 34.1 mmol). A solutionof 3-bromopyridine (4.71 g, 30 mmol) in THF (5 ml) was added dropwisetrying to keep the temperature below −70° C. The reaction was veryexothermic, a solid precipitated and THF (2 ml) was added to improvestirring. The temperature rose to −45° C., after cooling to −60° C. andadded remaining pyridine. DMF (2.49 g) in THF (15 ml) was added and thereaction stirred at −65° C. for 30 minutes. Water was added to quenchthe reaction and the reaction allowed to warm to ambient temperature.The reaction was partitioned between ethyl acetate/water and the aqueouslayer extracted with ethyl acetate. The organic layers were combined,dried (MgSO₄) and evaporated and the residue was subjected tochromatography (eluting with diethyl ether/hexane) to give3-bromo-4-pyridinecarbaldehyde (1.4 g, 76%).

[0472] MS(CI⁺): 186 [M+H]⁺.

[0473] Benzyldiethylphosphonate (1.94 g, 8.5 mmol) in THF (20 ml) wastreated with lithium bis(trimethylsilyl)amide (8.6 ml, 1 M). Thereaction was stirred for 1.5 hours and a solution of3-bromo-4-pyridinecarbaldehyde (1.4 g, 7.7 mmol) in THF (20 ml) added.The reaction was allowed to stand at ambient temperature for 18 hours,then partitioned between ethyl acetate/water. The organic layer wasdried (MgSO₄) and evaporated and the residue purified by chromatography(eluting with diethyl ether/hexane to give3-bromo-4-(2-phenylethenyl)pyridine (0.77 g, 39%)

[0474] MS(CI⁺): 260 [M+H]⁺.

[0475] 3-Bromo-4-(2-phenylethenyl)pyridine (0.74 g, 2.9 mmol) wasdissolved in DMF (1.4 ml). The solution was treated with tert-butyl4-ethynylbenzoate (0.93 g, 4.6 mmol), copper (III) iodide (0.023 g, 0.21mmol) and triethylamine (0.64 g, 6.3 mmol). The reaction mixture wasdegassed by bubbling through argon and the catalyst, bistriphenylphosphinepalladium dichloride (0.03 g, 0.043 mmol), was added. Thereaction was heated to 90-100° C. for 3 hours and then partitionedbetween ethyl acetate and water. The organic layer was washed with water(3×), dried (MgSO₄) and evaporated. The residue was purified bychromatography (eluting with ethylacetate/hexane) to give tert-butyl4-[2-(4-(2-phenylethenyl)-3-pyridyl)ethynyl]benzoate as a dark oil (0.36g, 33%).

[0476] MS [CI⁺]: 382 [M+H]⁺

[0477] tert-Butyl 4-[2-(4-(2-phenylethenyl)-3-pyridyl)ethynyl]benzoate(0.360 g, 0.95 mmol) was dissolved in ethanol/THF 1:1 (10 ml) andtreated with palladium on carbon (10%, 0. 13 g). The reaction was placedunder a hydrogen atmosphere and stirred at ambient temperature for 6hours. The reaction was then filtered and evaporated to give tert-butyl4-[2-(4-phenethyl-3-pyridyl)ethyl]benzoate (0.36 g).

[0478] MS(CI⁺): 388 [M+H]⁺.

EXAMPLE 32

[0479] 4-[3-(2-(phenylthio)phenyl)propyl]benzoic Acid

[0480] The title compound was prepared from the corresponding ethylester using a similar method to that of example 24 (A) except usingethanol in place of methanol. The title product was crystallised fromhexane/ether (9:1) to give white platelets m.p. 90-91° C.

[0481] NMR (200 MHz, DMSO-d₆) δ 1.86 (m, 2H); 2.6-2.9 (m, 4H); 7.1-7.4(m, 11H); 7.85 (d, J=8 Hz, 2H); 12.7 (broad s, 1H).

[0482] MS (FAB⁻): 347 (M−H)⁻ Elemental Analysis: Calc % C 75.8: H, 5.8;S, 9.2 Found % C 75.9; H, 5.8; S, 9.6

[0483] The starting material was prepared as follows:

[0484] To a solution of 4-carboxyphenethyl triphenylphosphonium bromide(11.2 g, 22.8 mmol) in THF (200 ml) under argon, was added a 1M solutionof lithium hexamethyldisilazide (50 ml) in THF at 20° C., giving a deepred colour. After stirring for 30 minutes, the reaction was treated witha solution of 2-bromobenzaldehyde (4.0 g, 21.6 mmol) in THF (15 ml) andstirred for a further 30 minutes at 20° C. The solution was poured ontoa stirred mixture of water (100 ml) and ether (100 ml). The layers wereseparated and the aqueous portion washed again with ether (100 ml),acidified with 1N HCl and extracted with ether (100 ml). The etherextracts were dried over anhydrous magnesium sulphate and “flashed”through a pad of silica to remove impurities, rinsing with furtherportions of ether. The filtrates were evaporated to give4-[3-(2-bromophenyl)prop-2-en-1-yl]benzoic acid (6.1 g) as a yellow gum,which slowly solidified.

[0485] To a solution of 4-[3-(2-bromophenyl)prop-2-en-1-yl]benzoic acid(5.8 g) in ethyl acetate (100 ml) was added 5% palladium-barium sulphatecatalyst (1.4 g) and the stirred mixture sealed in a hydrogen atmospherefor 50 hours at S.T.P. The mixture was filtered and evaporated atreduced pressure to give a solid (5.0 g) which was crystallised from 5%aqueous methanol (150 ml) to give 4-[3-(2-bromophenyl)propyl]benzoicacid (4.0 g) as white rhombs.

[0486] NMR (200 MHz, DMSO-d₆) δ:1.90 (m, 2H); 2.70 (m, 4H); 7.15 (m,1H); 7.32 (m, 4H); 7.57 (d, J=7 Hz, 1H); 7.87 (d, J=8 Hz, 2H).

[0487] MS (CI⁺): 319/321 (M+H)⁺(1×Br) Analysis: Calc % C 60.2; H, 4.7;Br 25.0 Found % C 60.1; H, 4.7; B 24.7

[0488] To a solution of 4-[3-(2-bromophenyl)propyl]benzoic acid (2.0 g)in a mixture of chloroform (50 ml) and ethanol (50 ml) was addeddropwise, with stirring, concentrated sulphuric acid (98% w/v, 5.0 ml)and the resulting solution allowed to stand for 40 hours at 20° C. Thesolution was poured onto a stirred mixture of chloroform (100 ml) andsaturated sodium bicarbonate. The organic layer was separated, driedover anhydrous magnesium sulphate and evaporated to give ethyl4-[3-(2-bromophenyl)propyl)benzoate (2.3 g).

[0489] To a solution of ethyl 4-[3-(2-bromophenyl)propyl)benzoate (1.0g, 2.9 mmol) in NMP (10 ml), sealed and stirred under argon, was addeddiphenyl disulphide (1.5 mmol) and activated copper powder (0.2 g). Themixture was heated at 180° C. for 16 hours, cooled to 20° C. and pouredinto a mixture of ether (100 ml), water (100 ml) and ethylene diamine(3.0 ml). The organic layer was separated, dried over anhydrousmagnesium sulphate and “flashed” through a pad of silica, rinsing withether. The filtrates were evaporated to give ethyl4-[3-(2-(phenylthio)phenyl)propyl]benzoate as an oil (1.0 g).

[0490] NMR (200 Mhz, DMSO-d₆) δ:1.32 (t, J=7 Hz, 3H); 1.83 (m, 2H);2.6-2.8 (m, 4H); 4.30 (q, J=7 Hz, 2H); 7.1-7.4 (m, 1H); 7.86 (d, J=8 Hz,2H).

[0491] MS (CI⁺): 376 M⁺

EXAMPLE 33

[0492] 2-Hydroxy-4-[(2-phenethyl)phenethyl]benzoic Acid

[0493] A solution of methyl 2-hydroxy-4-[2-(phenethyl)phenethyl]benzoate(0.25 g) in THF (5 ml) and methanol (5 ml) containing aqueous 2N sodiumhydroxide (5 ml) was heated under reflux for 2 hours. The reactionmixture was evaporated to small volume and acidified with aqueous 2Nhydrochloric acid. The mixture was extracted three times with ethylacetate (25 ml each time) and the combined extracts were washed withbrine and dried over anhydrous magnesium sulphate. The solid obtained onremoval of the solvent was crystallised from a mixture of diethyl etherand hexane to give 2-hydroxy-4-[(2-phenethyl)phenethyl]benzoic acid (0.2g), m.p. 134-7° C.

[0494] The starting material was prepared as follows:

[0495] (A) Oxalyl chloride (9.1 ml) was added to a suspension of2-bibenzylcarboxylic acid (20 g) in dichloromethane (200 ml) followed by0.1 ml of DMF. The mixture was stirred for 15 hours and evaporated todryness. The residue was dissolved in diglyme (150 ml) and cooled to−70° C. under argon. Lithium tri-t-butoxyaluminohydride (177 ml of a0.5M solution in diglyme) was added dropwise such that the temperatureof the reaction mixture did not exceed −65° C. The reaction mixture wasstirred for a further 2 hours at −70° C. and then poured onto ice. Theslurry obtained was acidified (HCl) and extracted with diethyl ether(3×75 ml). The combined ether extracts were washed with brine and dried(MgSO₄). The solvent was removed and the residue dissolved in petroleumether (BP 60-80° C.) and washed once with aqueous saturated sodiumbicarbonate, five times with water and twice with brine then dried.Removal of the solvent gave an oil which was purified by chromatographyon silica, eluting with dichloromethane-hexane (1:1 v/v), to give2-(phenethyl)benzaldehyde, (4.83 g).

[0496] (B) To a suspension of(3-acetyl-4-methoxycarbonyl)benzyltriphenyl phosphonium bromide (13.7 g)in THF (40 ml) under argon was added dropwise over 30 minutes a 1Msolution of lithium bis (trimethylsilyl) amide (52.35 ml) in THF. Themixture was stirred for 30 minutes, cooled to 0° C. and2-(phenethyl)benzaldehyde (4.83 g) dissolved in THF (20 ml) was addeddropwise over 30 minutes. The reaction mixture was allowed to warm toambient temperature and was stirred for a further 15 hours, then pouredinto water, acidified with hydrochloric acid and the mixture wasextracted with ethyl acetate (3×50 ml). The combined ethyl acetateextracts were washed with aqueous saturated sodium bicarbonate solutionand brine and dried (MgSO₄). Removal of the solvent gave an oil whichwas subjected to chromatography on silica, eluting with a mixture ofdichloromethane and hexane (1:1 v/v) to give trans methyl2-hydroxy-4-[2-(2-(phenethyl)phenyl)ethenyl]benzoate (2.0 g).

[0497] A solution of methyl2-hydroxy-4-[2-(2-(phenethyl)phenyl)ethenyl]benzoate [0.98 g] in ethanol(10 ml) and THF (10 ml) containing 10% palladium on carbon was stirredunder an atmosphere of hydrogen (balloon) for 14 hours. The catalyst wasremoved by filtration and the filtrate evaporated to dryness to givemethyl 2-hydroxy 4-[2-(2-phenethyl)phenethyl]benzoate as a gum.

EXAMPLE 34

[0498] 4-[3-(2-benzylphenyl)propyl]benzoic Acid

[0499] A solution of 4-[3-(2-benzylphenyl)prop-1-enyl]benzoic acid (6.43g) in THF (50 ml) containing 10% palladium on carbon (1 g) was stirredunder an atmosphere of hydrogen (balloon) for 15 hours. The catalyst wasremoved by filtration and the residue obtained on removal of the solventwas purified by chromatography on silica, eluting with 5% methanol indichloromethane, to give 4-[3-(2-benzylphenyl)propyl]benzoic acid, m.p.135-6° C.

[0500] 4-[3-(2-Benzylphenyl)prop-1-enyl]benzoic acid was prepared byreaction of 2-benzylbenzaldehyde with4-carboxyphenethyltriphenylphosphonium bromide using a similar method tothat of example 33(B) to give a gum. [2-Benzylbenzaldehyde (an oil) wasobtained from 2-benzylbenzoic acid using a similar method to that ofexample 33(A)].

EXAMPLE 35

[0501] 4-[N-(2-Benzyloxyphenyl)aminomethyl]benzoic Acid

[0502] (A) A mixture of methyl4-[N-(2-benzyloxyphenyl)aminomethyl]-benzoate (2 g), 2N sodium hydroxidesolution (14.4 ml), methanol (10 ml) and THF (10 ml) was heated atreflux for 30 minutes. Half the solvent was evaporated and the mixtureacidified with acetic acid. The resulting solid was filtered, dried andre-crystallised from methanol (yield 1.1 g, mpt 163° C.).

[0503] The starting material was prepared as follows:

[0504] (B) 2-Nitrophenol (50 g), benzyl bromide (61.5 g) and potassiumcarbonate (99.3 g) were stirred in acetone for 72 hours. The mixture wasfiltered and the solvent evaporated to give a solid (86.1 g), the solidwas mixed with ferric chloride (5 g) and water (200 ml) in methanol (200ml) and heated at 700C. Iron (69.4 g) was added in portions over 1 hour.The mixture was heated at 80° C. for 1.5 hours, cooled and mixed withdiethyl ether (500 ml). The mixture was filtered through Celite, washedwith 2N NaOH (3×100 ml) and the organic layer separated, dried (MgSO₄),filtered and evaporated to give 2-benzyloxybenzamine (68.7 g).

[0505] 2-Benzyloxybenzamine (10 g) and methyl 4-formylbenzoate (8.2 g)were heated at 100° C. for 3 hours, the mixture cooled to ambienttemperatrue dissolved in ethanol (200 ml) and sodium borohydride (1.85g) added. The mixture was stirred for 18 hours, the solvent volumereduced by half by evaporation, poured into water (200 ml) and acidifiedwith acetic acid. The mixture was extracted with dichloromethane (3×100ml), the extracts washed with saturated aqueous NaHCO₃ dried (MgSO₄) andevaporated. The residue was purified by chromatography eluting with 80%CH₂Cl₂/hexane to give methyl4-[N-(2-benzyloxyphenyl)aminomethyl]benzoate (14 g).

EXAMPLE 36

[0506] 4-[N-(2-Benzyloxyphenyl)-N-ethylaminomethyl]benzoic Acid

[0507] (A) The title compound was prepared from methyl4-[N-(2-benzyloxyphenyl)-N-ethylaminomethyl]benzoate (12.5 g) by asimilar method to that described in Example 35. (yield 4.2 g).

[0508] The starting material was prepared as follows:

[0509] (B) To a suspension of NaH (1.38 g, 50% dispersion in oil) in DMF(50 ml) at 0° C. was added a solution of methyl4-[N-(2-benzyloxyphenyl)aminomethyl] benzoate (10 g) in DMF (100 ml).

[0510] The mixture was stirred at 0° C. for 30 minutes, then ethyliodide was added (4.5 g) and the mixture stirred at ambient temperaturefor 18 hours. The solvent was evaporated, the residue dissolved in ethylacetate (200 ml) and washed with water (2×50 ml) and brine, dried(MgSO₄) and evaporated to give methyl4-[N-(2-benzyloxyphenyl)-N-ethylaminomethyl]benzoate (12.5 g).

EXAMPLE 37

[0511] 4-[N-(2-Benzyloxy-5-bromophenyl)aminomethyl]benzoic Acid

[0512] (A) The title compound (mpt 216-217° C.) was prepared using asimilar process to that described in Example 35 but from4-bromo-2-nitrophenol.

EXAMPLE 38

[0513] 4-[N-(2-Benzyloxy-5-bromophenyl)-N-ethylaminomethyl]benzoic Acid

[0514] (A) The title compound (mpt 94.5-95.0C) was prepared by a similarprocess to that described in Example 36 from methyl4-[N-(2-benzyloxy-5-bromophenyl)-N-ethylaminomethyl]benzoate.

EXAMPLE 39

[0515] 4-[1-(N-(2-Benzyloxy-5-bromophenyl)-amino)ethyl]benzoic Acid

[0516] (A) The title compound (mpt 186.5-187.0° C.) was prepraed fromethyl 4-[1-(N-(2-benzyloxy-5-bromophenyl)amino)ethyl]benzoate using asimilar process to that of Example 35(A). The product was purified bycrystallisation from ethyl acetate/hexane.

[0517] The starting material was prepared as follows:

[0518] (B) A mixture of 2-benzyloxy-5-bromobenzamine (2.0 g) and methyl4-acetylbenzoate (1.28 g) was heated at 150° C. for 3.5 hours. Thereaction mixture was purified by MPLC eluting with 1:1 CH₂Cl₂: hexane togive a solid (0.4 g). The material was dissolved in TFA (7 ml) andcooled to 0° C. BH₃.THF (1.77 ml; 1M solution in THF) was addeddropwise. The reaction was quenched with water (1 ml) and the pHadjusted to about 9 with 2N NaOH solution. The mixture was extractedwith ethyl acetate (2×50 ml), the extracts washed with brine, dried(MgSO₄), filtered and evaporated. The residue was purified by MPLCeluting with CH₂Cl₂: hexane (1:1) to give ethyl4-[—(N-(2-benzyloxy-5-bromophenyl)amino)ethyl]benzoate.

EXAMPLE 40

[0519] 4-[1-(N-(2-Benzyloxy-4-bromophenyl)-N-methylamino)ethyl]benzoicAcid

[0520] (A) The title compound (mpt 181.5-182° C.) was prepared fromethyl 4[1-(N-(2-benzyloxy-4-bromophenyl)-N-methylamino)ethyl]benzoate bya similar process to that of Example 35(A).

[0521] (B) The starting material was prepared from ethyl4-[1-(N-(2-benyzloxy-5-bromophenyl)amino)ethyl]benzoate using a processsimilar to that of Example 36(A), except using methyl iodide in place ofethyl iodide. The product, ethyl4-[1-(N-(2-benzyloxy-4-bromophenyl)N-methylamino)ethyl]benzoate, was purified by MPLC eluting withdichloromethane.

EXAMPLE 41

[0522]2-[N-(2-Benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridinecarboxylicAcid

[0523] (A) tert-Butyl2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridinecarboxylate(800 mg) and trifluoroacetic acid (20 ml) in dichloromethane (20 ml) washeated at reflux for 30 minutes. The solvent was evaporated and theresidue crystallised from a mixture of dichloromethane and diethyl ether(1:2) to give the title compound (600 mg) mpt 214° C. (decomp).

[0524] The starting material was prepared as follows:

[0525] (B) A mixture of 2-bromomethyl-4-bromophenyl benzyl ether (0.28moles) and NaCN (16 g) in DMF (200 ml) was stirred at ambienttemperature for 16 hours, then heated at 100° C. for 5 hours. A further2 g of NaCN was added and the reaction heated for 5 hours at 100° C. Themixture was diluted with water (200 ml) and stirred (1 hour). Theresulting solid was filtered off and recrystallised from methanol togive 4-bromo-2-cyanomethylphenyl benzyl ether (48 g) mpt. 75-76° C.

[0526] (C) To a mixture of NaBH₄ (6.0 g) in THF (100 ml) was addeddropwise trifluoroacetic acid (18 ml) at 0° C. (ice bath).4-Bromo-2-cyanomethylphenyl benzyl ether (10 g) was added and themixture stirred at ambient temperature for 18 hours. The reaction wasquenched with water (100 ml), the pH adjusted to 13 with 2N aqueous NaOHsolution, and extracted with diethyl ether. The diethyl ether extractswere dried (MgSO₄) and evaporated to give 2-(2-aminoethyl)-4-bromophenylbenzyl ether (11.0 g) as a yellow gum.

[0527] (D) A mixture of 2-(2-aminoethyl)-4-bromophenyl benzyl ether (3g), tert-butyl 2-chloro-5-pyridinecarboxylate (2.1 g) (prepared from theacid by standard procedures), and potassium carbonate (1.4 g) inN-methylpyrrolidone (20 ml) was heated at 120° C. for 16 hours. To thereaction mixture was added diethyl ether (200 ml) and water (200 ml),the layers separated, the organic layer washed with water, dried(MgSO₄), filtered and evaporated. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/ethyl acetatemixtures (100:0, 95:5) to give tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)amino]-5-pyridinecarboxylate (1.0 g).

[0528] (E) A mixture oftert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)-amino]-5-pyridinecarboxylate(850 mg), and sodium hydride (110 mg, 50% dispersion in oil) in DMF (20ml) was stirred for 15 minutes then iodoethane (150 ml) was added andthe mixture sitrred for 2 hours. The mixture was diluted with diethylether (50 ml) washed with water, dried (MgSO₄), filtered through silicagel, evaporated and the residue re-dissolved in dichloromethane andevaporated to give tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridine carboxylate(800 mg).

EXAMPLE 42

[0529] The compounds listed in the table were prepared from theappropriate ester compounds using a similar method to that described inExample 41, paragraph A.

Compound No. R adducts Footnote 1 H CF₃CO₂H a 2 Me CF₃CO₂H a, b 3—CH₂CH═CH₂ CF₃CO₂H c, d

[0530] N-allylamino]-5-pyridinecarboxylate was prepared from tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)amino]-S-pyridinecarboxylate using asimilar method to that of Example 1 (E) but replacing iodoethane withallyl bromide.

EXAMPLE 43

[0531] 4-[N-(2-Benzyloxy-5-bromophenethyl)-N-methylamino]benzoic Acid

[0532] (A) A mixture of ethyl4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino] benzoate (1.0 g) and2N NaOH (5 ml) in ethanol (50 ml) was heated at reflux for 4 hours. Thesolution was evaporated, acidified with 2N HCl solution and the titleproduct filtered off as a white powder (100%).

[0533] The starting material was prepared as follows:

[0534] (B) To a mixture of 2-benzyloxy-5-bromophenylacetic acid (3.2 g)in toluene (100 ml) was added thionyl chloride (1.0 ml) and DMF (3drops). The reaction was stirred at 80° C. for 1 hour and cooled toambient temperature ethyl 4-aminobenzoate (2.0 g) and triethylamine (2ml) were added to the reaction mixture with stirring. After standing for18 hours, the mixture was diluted with dichloromethane and washed withwater, 1N HCl solution, water and sautrated aqueous NaHCO₃ solution. Theorganic extract was dried (MgSO₄), filtered and evaporated and theresidue purified by trituration with diethyl ether to give ethyl4-[2-benzyloxy-5-bromophenylacetamido]benzoate (2.0 g) mpt. 174-176° C.

[0535] (C) A mixture of ethyl4-[2-benzyloxy-5-bromophenylacetamido]-benzoate (2.5 g) and BH₃. THF (10mM) in THF (60 ml) was stirred at 50° C. for 2 hours, cooled (ice bath)and diluted with 2N HCl solution (10 ml) and diethyl ether (50 ml). Theorganic layer was separated, dried (MgSO₄) and evaporated. The residuewas purified by chromatography on silica gel eluting withdichloromethane to give ethyl4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate (1.4 g).

[0536] (D) Ethyl 4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate wasconverted to ethyl4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]benzoate using asimilar method to that described in Example 41(D) except methyl iodidewas used in place of iodoethane.

EXAMPLE 44

[0537] 4-[N-(2-Benzyloxy-5-bromophenethyl)amino]benzoic Acid

[0538] The title compound was prepared from ethyl4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate using a similar methodto that of Example 43(A).

EXAMPLE 45

[0539]N-Propyl-4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]benzamide andN-(3-pyridyl)-4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]-benzamide

[0540] A mixture of4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]benzoic acid (700 mg),triethylamine (0.6 ml) and oxalyl chloride (0.2 ml) in dichloromethane(50 ml) was stirred for 30 minutes. The solvent was evaporated and theresidue dissolved in dichloromethane (60 ml). The resulting solution wasdivided into two portions. One portion was mixed with n-propylamine (0.5ml) and the second with 3-aminomethylpyridine (0.5 ml). Each reactionwas stirred for 1 hour, evaporated and the residues purified separatelyby chromatography on silica gel eluting the product of the firstreaction with dichloromethane: ethyl acetate (4:1) and the second withethyl acetate: methanol (98:2). The first product,N-propyl-4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino] benzamide(170 mg), was purified by crystallisation form dichloromethane/hexanemixtures. The second product,N-(3-pyridyl)-4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]-benzamide(100 mg) did not require further purification after chromatography.

EXAMPLE 46

[0541] 4-[N-(2-(2-Benzyloxy-5-bromophenyl)ethyl)-N-ethylamino]benzoicAcid

[0542] 4-[N-(2-(2-benzyloxy-5-bromophenyl)ethyl)-N-ethylamino]-benzoicacid (mpt. 175° C.) was obtained from 2-benzyloxyphenylacetic acid by asimilar process to that described in Example 43.

EXAMPLE 47

[0543] 4-[N-(2-(2-Benzyloxyphenyl)ethyl)-N-ethylamino]benzoic acid Ethyl4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate was dissolved ina solution of methanol (20 ml) and tetrahydrofuran (20 ml). To thissolution was added aqueous 2N sodium hydroxide (10.5 ml) and the mixtureheated at reflux for 24 hours; cooled and the volume reduced byevaporation to half the original volume. Water (20 ml) was added and themixture acidified with acetic acid. The resulting solid was filtered anddried under vacuum at 60° C. to give the title product (950 mg) m.p.175° C.

[0544] The starting material was prepared as follows:

[0545] 2-Benzyloxyphenylacetic acid (5 g) was dissolved indichloromethane and oxalyl chloride (2.6 g) added. Dimethyl formamide (2drops) was added and the mixture was stirred at ambient temperature for18 hours. The solvent was evaporated and the residue redissolved indichloromethane (50 ml) and added to an ice cold solution of ethyl4-(N-ethylamino)benzoate and triethylamine in dichloromethane (50 ml).The reaction mixture was allowed to warm to ambient temperature andwashed with 2N hydrochloric acid (3×50 ml), aqueous sodium hydrogencarbonate solution (1×50 ml), dried over MgSO₄ and evaporated to giveethyl 4-[N-(2-benzyloxybenzylcarbonyl)-N-ethylamino]benzoate (8.1 g).

[0546] Ethyl 4-[N-(2-benzyloxybenzylcarbonyl)-N-ethylamino]benzoate (8.1g) was dissolved in THF (20 ml) and IM borane tetrahydrofuran complexadded. The reaction mixture was heated at reflux for 1 hour and cooled.2N Hydrochloric acid (20 ml) was added. The volume of the reactionmixture was reduced to half the original by evaporation. Water (100 ml)was added and made basic (pH 8) by the addition of solid potassiumcarbonate and the mixture extracted with diethyl ether (3×30 ml). Thecombined extracts were dried over MgSO₄ and evaporated. The residue waspurified by MPLC, eluting with 1:1 dichloromethane/hexane, to give ethyl4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate (1.8 g) m.p. 76°C.

1. A compound according to formula (I);

wherein: A is phenyl or pyridyl optionally substituted with L, where Lis a moiety selected from trifluoromethyl, nitro, hydroxy, amino, cyano,benzenesulphonamido, aminosulphonyl, oxazolyl, pyridyl, thiazolyl,pyrimidyl, pyrazinyl, pyridazinyl, halo, (C₁-C₆)alkyl optionallysubstituted with a group selected from hydroxy, amino, halo, nitro andcyano, (C₁-C₆)alkoxy, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino,S(O)_(p)CF₃ wherein p is 0, 1 or 2, carbamoyl, S(O)_(p)(C₁-C₆)alkyl,(C₁-C₄)alkylcarbamoyl, di(C₁-C₄)alkylcarbamoyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₂-C₄)alkenylamino,N-(C₂-C₄)alkenyl-N—(C₁-C₄)alkylamino, di-(C₂-C₄)alkenylamino,S(O)_(p)(C₂-C₆)alkenyl, (C₂-C₄)alkenylcarbamoyl,di(C₂-C₄)alkenylcarbamoyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl(C₂-C₃)alkenyl,(C₅-C₇)cycloalkenyl, (C₅-C₇)cycloalkenyl(C₁-C₃)alkyl,(C₅-C₇)cycloalkenyl(C₂-C₃)alkenyl, (C₅-C₇)cycloalkenyl(C₂-C₃)alkynyl,(C₁-C₄)alkoxycarbonylamino, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyl(N—(C₁-C₄)alkyl)amino, (C₁-C₄)alkanesulphonamido,(C₁C₄)alkylaminosulphonyl, di(C₁-C₄)alkylaminosulphonyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyloxy, (C₁-C₆)alkanoyl,formyl(C₁-C₄)alkyl, trifluoro(C₁-C₃)alkylsulphonyl,hydroxyimino(C₁-C₆)alkyl, (C₁-C₄)alkoxyimino(C₁-C₆)alkyl and(C₁-C₆)alkylcarbamoylamino; B is phenyl; D is phenyl optionallysubstituted with L; the —Z—B—R¹ and —X—D groups are positioned in a 1-2relationship to one another on phenyl or pyridyl ring A; the phenyl-ringA atom positioned ortho to the —X— linking group, in the 3-positionrelative to the —Z— linking group, is not substituted; R¹ is positionedon the phenyl-ring B in a 1-3 or 1-4 relationship with the —Z— linkinggroup; R¹ is carboxy; Z is selected from —CH(R^(3a))CH(R^(3a))N(R²)—,—CH(R^(3a))N(R²)— and —CH(R^(3a))S— wherein R³a is selected from(C₁-C₄)alkyl and the left-most atom of each aforesaid moiety is attachedto A; or Z is selected from —CH(R³)N(R²)CH(R³)— and —N(R²)CH(R³)—wherein R³ is selected from hydrogen or (C₁-C₄)alkyl and the left-mostatom of each aforesaid moiety is attached to A; X is selected from—OCH₂—, —CH₂CH₂— and —N(R²)CH₂— wherein the left most atom of eachaforesaid moiety is attached to A, and R² is selected from hydrogen, or(C₁-C₆)alkyl, with the proviso that when Z is —CH(R 3)N(R²), X is not—O—CH₂—; N-oxides of —NR², where chemically possible; S-oxides ofsulphur-containing rings where chemically possible; orpharmaceutically-acceptable salts or in vivo-hydrolysable esters oramides thereof.
 2. A compound according to claim 1, wherein A isunsubstituted or substituted with a group selected from chloro, bromoand methanesulphonyl.
 3. A compound according to claim 2, wherein A issubstituted with bromo.
 4. A compound according to claim 1, wherein D isunsubstituted or substituted with a group selected from halo, nitro,hydroxy, cyano, (C₁-C₆)alkyl, amino, (C₁-C₆)alkoxy and carbamoyl.
 5. Acompound according to claim 1, selected from:4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoic acid;4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]benzoic acid;4-[N-(2-benzyloxyphenyl)aminomethyl]benzoic acid;4-[N-(2-benzyloxyphenyl)-N-ethylaminomethyl]benzoic acid;4-[N-(2-benzyloxy-5-bromophenyl)aminomethyl]benzoic acid;4-[N-(2-benzyloxy-5-bromophenyl)-N-ethylaminomethyl]benzoic acid; or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1, and a pharmaceutically-acceptable carrier.
 7. A method ofrelieving pain comprising administering an effective amount of acompound according to claim 1, to a patient in need thereof.
 8. Aprocess for preparing a compound according to claim 1, which processcomprises: reacting a compound of the formula (VIII)

with a compound of the formula R⁸X², wherein: B, A, X and D are asdefined in claim 15; Y is selected from, —CH(R³)NHCH(R³)— and—NHCH(R³)—; R⁷ is R¹ or protected R¹, R⁸ is R² or protected R², and X2is a leaving group, and thereafter if necessary performing one or moreof the following steps forming a pharmaceutically-acceptable salt;forming an in vivo-hydrolysable ester or amide, or converting onesubstituent into another substituent.
 9. A process for preparing acompound according to claim 1, which process comprises: reacting acompound of the formula (IX) with a compound of the formula (X):

wherein: B, A, X and D are as defined in claim 15; R⁷ is R¹ or protectedR¹, R⁸ is R² or protected R², R¹¹ is a removable activating group; R¹²is a leaving group, and q and r are independently 0 or 1 with theproviso that q and r are not both 1, and thereafter if necessaryperforming one or more of the following steps forming apharmaceutically-acceptable salt; forming an in vivo-hydrolysable esteror amide, or converting one substituent into another substituent.
 10. Acompound selected from:4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-tertbutoxycarbonylphenyl)-aminomethyl]benzoicacid;4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoicacid; and4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-carboxybenzyl)amino]benzoic acid;or a pharmaceutically acceptable salt thereof.
 11. A compound selectedfrom: 4-[N-(2-(phenethyl)benzyl)-N-ethylamino]benzoic acid;4-[1-(N-(2-benzyloxy-5-bromophenyl)-amino)ethyl]benzoic acid;4-[1-(N-(2-benzyloxy-4-bromophenyl)-N-methylamino)ethyl]benzoic acid;4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]benzoic acid;4-[N-(2-(2-benzyloxy-5-bromophenyl)ethyl)-N-ethylamino]benzoic acid, and4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoic acid; or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 10, and a pharmaceutically-acceptable carrier.
 13. A method ofrelieving pain comprising administering an effective amount of acompound according to claim 10, to a patient in need thereof.
 14. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 11, and a pharmaceutically-acceptable carrier.
 15. Amethod of relieving pain comprising administering an effective amount ofa compound according to claim 11, to a patient in need thereof.